Enhancer of Zeste Homolog 2 inhibitors

ABSTRACT

This invention relates to novel substituted benzamide according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.

FIELD OF THE INVENTION

This invention relates to substituted benzamide compounds which inhibitEnhancer of Zeste Homolog 2 (EZH2) and thus are useful for inhibitingthe proliferation of and/or inducing apoptosis in cancer cells.

BACKGROUND OF THE INVENTION

Epigenetic modifications play an important role in the regulation ofmany cellular processes including cell proliferation, differentiation,and cell survival. Global epigenetic modifications are common in cancer,and include global changes in DNA and/or histone methylation,dysregulation of non-coding RNAs and nucleosome remodeling leading toaberrant activation or inactivation of oncogenes, tumor suppressors andsignaling pathways. However, unlike genetic mutations which arise incancer, these epigenetic changes can be reversed through selectiveinhibition of the enzymes involved. Several methylases involved inhistone or DNA methylation are known to be dysregulated in cancer. Thus,selective inhibitors of particular methylases will be useful in thetreatment of proliferative diseases such as cancer.

EZH2 (human EZH2 gene: Cardoso, C, et al; European J of Human Genetics,Vol. 8, No. 3 Pages 174-180, 2000) is the catalytic subunit of thePolycomb Repressor Complex 2 (PRC2) which functions to silence targetgenes by tri-methylating lysine 27 of histone H3 (H3K27me3). Histone H3is one of the five main histone proteins involved in the structure ofchromatin in eukaryotic cells. Featuring a main globular domain and along N-terminal tail, Histones are involved with the structure of thenucleosomes, a ‘beads on a string’ structure. Histone proteins arehighly post-translationally modified however Histone H3 is the mostextensively modified of the five histones. The term “Histone H3” aloneis purposely ambiguous in that it does not distinguish between sequencevariants or modification state. Histone H3 is an important protein inthe emerging field of epigenetics, where its sequence variants andvariable modification states are thought to play a role in the dynamicand long term regulation of genes.

Increased EZH2 expression has been observed in numerous solid tumorsincluding those of the prostate, breast, skin, bladder, liver, pancreas,head and neck and correlates with cancer aggressiveness, metastasis andpoor outcome (Varambally et al., 2002; Kleer et al., 2003; Breuer etal., 2004; Bachmann et al., 2005; Weikert et al., 2005; Sudo et al.,2005; Bachmann et al., 2006). For instance, there is a greater risk ofrecurrence after prostatectomy in tumors expressing high levels of EZH2,increased metastasis, shorter disease-free survival and increased deathin breast cancer patients with high EZH2 levels (Varambally et al.,2002; Kleer et al., 2003). More recently, inactivating mutations in UTX(ubiquitously transcribed tetratricopeptixe repeats X), a H3K27demethylase which functions in opposition to EZH2, have been identifiedin multiple solid and hematological tumor types (including renal,glioblastoma, esophageal, breast, colon, non-small cell lung, small celllung, bladder, multiple myeloma, and chronic myeloid leukemia tumors),and low UTX levels correlate with poor survival in breast cancersuggesting that loss of UTX function leads to increased H3K27me3 andrepression of target genes (Wang et al., 2010). Together, these datasuggest that increased H3K27me3 levels contribute to canceraggressiveness in many tumor types and that inhibition of EZH2 activitymay provide therapeutic benefit.

Numerous studies have reported that direct knockdown of EZH2 via siRNAor shRNA or indirect loss of EZH2 via treatment with the SAH hydrolaseinhibitor 3-deazaneplanocin A (DZNep) decreases cancer cell lineproliferation and invasion in vitro and tumor growth in vivo (Gonzalezet al., 2008, GBM 2009). While the precise mechanism by which aberrantEZH2 activity leads to cancer progression is not known, many EZH2 targetgenes are tumor suppressors suggesting that loss of tumor suppressorfunction is a key mechanism. In addition, EZH2 overexpression inimmortalized or primary epithelial cells promotes anchorage independentgrowth and invasion and requires EZH2 catalytic activity.(Kleer et al.,2003; Cao et al., 2008).

Thus, there is strong evidence to suggest that inhibition of EZH2activity decreases cellular proliferation and invasion. Accordingly,compounds that inhibit EZH2 activity would be useful for the treatmentof cancer.

SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I), andpharmaceutically acceptable salts thereof

Wherein

R¹and R² are selected independently from the group consisting ofhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl-(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl-(C₂-C₈)alkenyl, (C₅-C₈)cycloalkenyl,(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₅-C₈)cycloalkenyl-(C₂-C₈)alkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, heterocycloalkyl-(C₁-C₈)alkyl,heterocycloalkyl-(C₂-C₈)alkenyl, aryl, aryl-(C₁-C₈)alkyl,aryl-(C₂-C₈)alkenyl, heteroaryl, heteroaryl-(C₁-C₈)alkyl,heteroaryl-(C₂-C₈)alkenyl, halo, cyano, —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b), —C(O)NR^(a)NR^(a)R^(b), —SR^(a), —S(O)R^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b), wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted 1, 2 or 3 times by groups independently selectedfrom the group consisting of hydroxyl, halo, amino, nitro, (C₁-C₃)alkyl,(C₃-C₈)cycloalkyl, cyano, (C₁-C₃)alkoxy, —NR^(a)R^(b) and —CO₂R^(a);

R³ is H or halo;

R⁴ is selected from the group consisting of (C₁-C₃)alkoxy, (C₁-C₃)alkyl,hydroxyl, halo, cyano, (C₃-C₆)cycloalkyl, (C₃-C₆)heterocycloalkyl,NR^(a)R^(b), (C₁-C₃)haloalkyl, and (C₁-C₃) hydroxylalkyl;

R⁵ is selected from the group consisting of (C₄-C₈)alkyl, (C₃-C₈)alkoxy,(C₃-C₈)cycloalkyoxy-, (C₃-C₈)heterocycloalkyloxy-, (C₄-C₈)cycloalkyl,aryl, heteroaryl and NR^(a)R^(b), wherein said (C₄-C₈)alkyl,(C₃-C₈)alkoxy, (C₃-C₈)cycloalkyoxy-, (C₃-C₈)heterocycloalkyloxy-,(C₄-C₈)cycloalkyl, aryl or heteroaryl is optionally substituted by 1, 2or 3 groups independently selected from the group consisting ofhydroxyl, halo, amino, nitro, (C₁-C₃)alkyl, (C₃-C₈)cycloalkyl, cyano,(C₁-C₃)alkoxy and —CO₂R^(a);

R⁶ is selected from the group consisting of hydrogen, halo,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, —B(OH)₂, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, (C₅-C₈)cycloalkenyl,(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl,heterocycloalkyl, heterocycloalkyl-(C₁-C₈)alkyl, aryl,aryl-(C₁-C₈)alkyl, heteroaryl, heteroaryl-(C₁-C₈)alkyl, cyano,—C(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b), —C(O)NR^(a)NR^(a)R^(b),—SR^(a), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b),—NR^(a)NR^(a)C(O)R^(b), —NR^(a)NR^(a)C(O)NR^(a)R^(b),—NR^(a)NR^(a)C(O)OR^(a), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b),wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom the group consisting of —O(C₁-C₆)alkyl(R^(c))₁₋₂,—S(C₁-C₆)alkyl(R^(c))₁₋₂, —(C₁-C₆)alkyl(R^(c))₁₋₂,(C₁-C₈)alkyl-heterocycloalkyl-, (C₃-C₈)cycloalkyl-heterocycloalkyl-,halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b),—SR^(a), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a),—OC(O)NR^(a)R^(b), heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl-, and heteroaryl(C₁-C₄)alkyl-, wherein any aryl orheteroaryl moiety of said aryl, heteroaryl, aryl(C₁-C₄)alkyl, orheteroaryl(C₁-C₄)alkyl is optionally substituted by 1, 2 or 3 groupsindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, hydroxyl, (C₁-C₆)haloalkyl,cyano, —C(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b), —SR^(a), —S(O)R^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b);

each R^(c) is independently (C₁-C₄)alkylamino, —NR^(a)SO₂R^(b),—S(O)R^(a), —SO₂R^(a), —NR^(a)C(O)OR^(a), —NR^(a)R^(b), or —CO₂R^(a);

R^(a) and R^(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₈)cycloalkenyl,heterocycloalkyl, aryl, heteroaryl, wherein said (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl or heteroaryl group is optionally substituted by1, 2 or 3 groups independently selected from halo, hydroxyl,(C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino, —N((C₁-C₄)alkyl)₂, —CO₂H,—CO₂(C₁-C₄)alkyl, —CONH₂, —CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)₂,—SO₂(C₁-C₄)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, or —SO₂N((C₁-C₄)alkyl)₂;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring.

Second aspect of this invention relates to a method of inducingapoptosis in cancer cells of solid tumors; treating solid tumor cancers.

Third aspect of the invention relates to pharmaceutical preparationscomprising compounds of formula (I) and pharmaceutically acceptableexcipients.

In a fourth aspect, there is provided the use of a compound of formula(I) and/or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for use in the treatment of a disordermediated by inhibiting EZH2, such as inducing apoptosis in cancer cells.

In a fifth aspect there is provided methods of co-administering thepresently invented compounds of formula (I) with other activeingredients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula (I),

Wherein

R¹ and R² are selected independently from the group consisting ofhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl-(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl-(C₂-C₈)alkenyl, (C₅-C₈)cycloalkenyl,(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₅-C₈)cycloalkenyl-(C₂-C₈)alkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, heterocycloalkyl-(C₁-C₈)alkyl,heterocycloalkyl-(C₂-C₈)alkenyl, aryl, aryl-(C₁-C₈)alkyl,aryl-(C₂-C₈)alkenyl, heteroaryl, heteroaryl-(C₁-C₈)alkyl,heteroaryl-(C₂-C₈)alkenyl, halo, cyano, —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b), —C(O)NR^(a)NR^(a)R^(b), —SR^(a), —S(O)R^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b), wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted 1, 2 or 3 times by groups independently selectedfrom the group consisting of hydroxyl, halo, amino, nitro, (C₁-C₃)alkyl,(C₃-C₈)cycloalkyl, cyano, (C₁-C₃)alkoxy, —NR^(a)R^(b) and —CO₂R^(a);

R³ is H or halo;

R⁴ is selected from the group consisting of (C₁-C₃)alkoxy, (C₁-C₃)alkyl,hydroxyl, halo, cyano, (C₃-C₆)cycloalkyl, (C₃-C₆)heterocycloalkyl,NR^(a)R^(b), (C₁-C₃)haloalkyl, and (C₁-C₃) hydroxylalkyl;

R⁵ is selected from the group consisting of (C₄-C₈)alkyl, (C₃-C₈)alkoxy,(C₃-C₈)cycloalkyoxy-, (C₃-C₈)heterocycloalkyloxy-, (C₄-C₈)cycloalkyl,aryl, heteroaryl and NR^(a)R^(b), wherein said (C₄-C₈)alkyl,(C₃-C₈)alkoxy, (C₃-C₈)cycloalkyoxy-, (C₃-C₈)heterocycloalkyloxy-,(C₄-C₈)cycloalkyl, aryl or heteroaryl is optionally substituted by 1, 2or 3 groups independently selected from the group consisting ofhydroxyl, halo, amino, nitro, (C₁-C₃)alkyl, (C₃-C₈)cycloalkyl, cyano,(C₁-C₃)alkoxy and —CO₂R^(a);

R⁶ is selected from the group consisting of hydrogen, halo,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, —B(OH)₂, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, (C₅-C₈)cycloalkenyl,(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl,heterocycloalkyl, heterocycloalkyl-(C₁-C₈)alkyl, aryl,aryl-(C₁-C₈)alkyl, heteroaryl, heteroaryl-(C₁-C₈)alkyl, cyano,—C(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b), —C(O)NR^(a)NR^(a)R^(b),—SR^(a), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b),—NR^(a)NR^(a)C(O)R^(b), —NR^(a)NR^(a)C(O)NR^(a)R^(b),—NR^(a)NR^(a)C(O)OR^(a), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b),wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom the group consisting of —O(C₁-C₆)alkyl(R^(c))₁₋₂,—S(C₁-C₆)alkyl(R^(c))₁₋₂, —(C₁-C₆)alkyl(R^(c))₁₋₂,(C₁-C₈)alkyl-heterocycloalkyl-, (C₃-C₈)cycloalkyl-heterocycloalkyl-,halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b),—SR^(a), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a),—OC(O)NR^(a)R^(b), heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl-, and heteroaryl(C₁-C₄)alkyl-, wherein any aryl orheteroaryl moiety of said aryl, heteroaryl, aryl(C₁-C₄)alkyl, orheteroaryl(C₁-C₄)alkyl is optionally substituted by 1, 2 or 3 groupsindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, hydroxyl, (C₁-C₆)haloalkyl,cyano, —C(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b), —SR^(a), —S(O)R^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b);

each R^(c) is independently (C₁-C₄)alkylamino, —NR^(a)SO₂R^(b),—S(O)R^(a), —SO₂R^(a), —NR^(a)C(O)OR^(a), —NR^(a)R^(b), or —CO₂R^(a);

R^(a) and R^(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₈)cycloalkenyl,heterocycloalkyl, aryl, heteroaryl, wherein said (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl or heteroaryl group is optionally substituted by1, 2 or 3 groups independently selected from halo, hydroxyl,(C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino, —N((C₁-C₄)alkyl)₂, —CO₂H,—CO₂(C₁-C₄)alkyl, —CONH₂, —CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)₂,—SO₂(C₁-C₄)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, or —SO₂N((C₁-C₄)alkyl)₂;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to compounds of Formula (I),wherein R¹ is (C₁-C₆)alkyl, or a pharmaceutically acceptable saltsthereof

In another embodiment, this invention relates to compounds of Formula(I), wherein R² is (C₁-C₆)alkyl or benzyl, or a pharmaceuticallyacceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ and R² are methyl, R³ is hydrogen, or a pharmaceuticallyacceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen and R⁴ ischloro, or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen and R⁴ ismethyl, or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen, R⁴ is methyland R⁵ is selected from the group consisting of (C₃-C₈)alkoxy,(C₃-C₈)cycloalkyoxy-, (C₃-C₈)heterocycloalkyloxy-, heteroaryl andNR^(a)R^(b), wherein said (C₃-C₈)alkoxy, (C₃-C₈)cycloalkyoxy-,(C₃-C₈)heterocycloalkyloxy-, or heteroaryl is optionally substituted by1, 2 or 3 groups independently selected from the group consisting ofhydroxyl, halo, amino, nitro, (C₁-C₃)alkyl, (C₃-C₈)cycloalkyl, cyano,(C₁-C₃)alkoxy and —CO₂R^(a); or a pharmaceutically acceptable saltthereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen, R⁴ is methyland R⁶ is selected from the group consisting of hydrogen, cyano, halo,—SO₂(C₁-C₃)alkyl; pyridinyl, thiazolyl, and phenyl, wherein saidpyridinyl, thiazolyl or phenyl is optionally substituted by 1, 2 or 3groups independently selected from the group consisting of—O(C₁-C₆)alkyl(R^(c))₁₋₂, —S(C₁-C₆)alkyl(R^(c))₁₋₂,—(C₁-C₆)alkyl(R^(c))₁₋₂, (C₁-C₈)alkyl-heterocycloalkyl-,(C₃-C₈)cycloalkyl-heterocycloalkyl-, halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano,—C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b), —SR^(a), —S(O)R^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b),heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl-, andheteroaryl(C₁-C₄)alkyl-; or a pharmaceutically acceptable salt thereof.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen, R⁴ is methyland R⁵ is the group consisting of (C₃-C₈)alkoxy, (C₃-C₈)cycloalkyloxy-,(C₃-C₈)heterocycloalkyloxy-, and NR⁶R⁷; wherein R⁶ and R⁷ areindependently selected from groups consisting of hydrogen, (C₁-C₄)alkyl,hydroxyl(C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl- and —C(═O)(C₁-C₃)alkyl;or R⁶ and R⁷, taken together with the N to which they are attached, forma three to seven membered ring, wherein said ring is optionallysubstituted one to three times by R⁸; wherein said R⁸ is selected fromgroups consisting of (C₁-C₃)alkyl, halo and hydroxyl.

In another embodiment, this invention relates to compounds of Formula(I), wherein R¹ is methyl, R² is methyl, R³ is hydrogen, R⁴ is methyland R⁶ is selected from the group consisting of hydrogen, cyano, halo,—SO₂(C₁-C₃)alkyl, pyridinyl, thiazolyl, and phenyl; wherein saidpyridinyl, thiazolyl and phenyl may be optionally substituted by 1, 2 or3 groups independently selected from the group consisting of(C₁-C₃)alkyl, (C₁-C₃)alkoxy, optionally substituted heterocycloalkyl and—CH₂N(R⁹)₂, wherein each R⁹ is independently selected from the groupconsisting of hydrogen and (C₁-C₃)alkyl.

Specific compounds of this invention include:

-   5-Bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide;-   2-Methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-5-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]benzamide;-   5-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide;-   5-Bromo-2-methyl-3-[(1-methylethyl)amino]-N-{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}benzamide;-   2-Methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-5-[6-(methyloxy)-3-pyridinyl]benzamide;-   N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(methyloxy)-3-pyridinyl]benzamide;-   4′-[(Dimethylamino)methyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-methyl-5-[(1-methylethyl)amino]-3-biphenylcarboxamide;-   5-(6-Amino-3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide;-   N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(1-piperazinyl)-3-pyridinyl]benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide;-   5-Bromo-3-(sec-butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide;-   3-(sec-Butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide;-   5-Bromo-2-methyl-3-[methyl(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide;-   5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropyl(methyl)amino)-2-methylbenzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropyl(methyl)amino)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide;-   5-Bromo-3-(sec-butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide;-   3-(sec-Butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide;-   5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpyrrolidin-1-yl)benzamide;-   5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpiperidin-1-yl)benzamide;-   5-Bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide;-   5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide;-   3-[acetyl(1-methylpropyl)amino]-5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide;-   2,5-dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylpropyl)amino]benzamide;-   2,5-dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylethyl)oxy]benzamide;-   5-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-{[1-methyl-2-(methyloxy)ethyl]amino}benzamide;-   5-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(2-hydroxy-1-methylethyl)amino]-2-methylbenzamide;-   5-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)oxy]benzamide;-   5-chloro-3-(cyclopentyloxy)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide;-   2,5-dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-(1-methyl-1H-pyrazol-5-yl)benzamide;-   3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide;-   5-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3′-((dimethylamino)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy    -2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methyl-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3′-((dimethylamino)methyl)-5-isopropoxy-4-methyl-[1,1′-biphenyl]-3-carboxamide;-   3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-2-methylbenzamide;-   3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydrofuran-3-yl)oxy)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-methylpyrrolidin-3-yl)oxy)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzamide;-   3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(methylsulfonyl)benzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methyl-5-(methylsulfonyl)benzamide;-   3-(sec-butoxy)-5-cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide;-   5-cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide;-   3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-2-methylbenzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-5-methoxy-2-methylbenzamide;-   N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methylbenzamide.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the disclosed compounds containinga basic amine or other basic functional group may be prepared by anysuitable method known in the art, including treatment of the free basewith an inorganic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, or with anorganic acid, such as acetic acid, trifluoroacetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid or the like. Examples of pharmaceutically acceptablesalts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates,phenylpropionates, phenylbutrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates,such as xylenesulfonates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates and naphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or otheracidic functional group can be prepared by reacting with a suitablebase. Such a pharmaceutically acceptable salt may be made with a basewhich affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, quinine, quinoline, and basicamino acid such as lysine and arginine.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of this invention and these should beconsidered to form a further aspect of the invention. These salts, suchas oxalic or trifluoroacetate, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts.

The compound of Formula (I) or a salt thereof may exist instereoisomeric forms (e.g., it contains one or more asymmetric carbonatoms). The individual stereoisomers (enantiomers and diastereomers) andmixtures of these are included within the scope of the presentinvention. Likewise, it is understood that a compound or salt of Formula(I) may exist in tautomeric forms other than that shown in the formulaand these are also included within the scope of the present invention.It is to be understood that the present invention includes allcombinations and subsets of the particular groups defined hereinabove.The scope of the present invention includes mixtures of stereoisomers aswell as purified enantiomers or enantiomerically/diastereomericallyenriched mixtures. It is to be understood that the present inventionincludes all combinations and subsets of the particular groups definedhereinabove.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H,11C, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and 125I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as 3H, 14C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularlypreferred for their ease of preparation and detectability. 11C and 18Fisotopes are particularly useful in PET (positron emission tomography),and 125I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., 2H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

The invention further provides a pharmaceutical composition (alsoreferred to as pharmaceutical formulation) comprising a compound ofFormula (I) or pharmaceutically acceptable salt thereof and one or moreexcipients (also referred to as carriers and/or diluents in thepharmaceutical arts). The excipients are acceptable in the sense ofbeing compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof (i.e., the patient).

Pharmaceutical compositions may be in unit dose form containing apredetermined amount of active ingredient per unit dose. Such a unit maycontain a therapeutically effective dose of the compound of Formula (I)or salt thereof or a fraction of a therapeutically effective dose suchthat multiple unit dosage forms might be administered at a given time toachieve the desired therapeutically effective dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical compositions may beprepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example, by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous, or intradermal) routes. Such compositionsmay be prepared by any method known in the art of pharmacy, for example,by bringing into association the active ingredient with theexcipient(s).

When adapted for oral administration, pharmaceutical compositions may bein discrete units such as tablets or capsules; powders or granules;solutions or suspensions in aqueous or non-aqueous liquids; edible foamsor whips; oil-in-water liquid emulsions or water-in-oil liquidemulsions. The compound or salt thereof of the invention or thepharmaceutical composition of the invention may also be incorporatedinto a candy, a wafer, and/or tongue tape formulation for administrationas a “quick-dissolve” medicine.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders or granules are prepared bycomminuting the compound to a suitable fine size and mixing with asimilarly comminuted pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin or non-gelatinous sheaths. Glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate, solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate, or sodium carbonate can also beadded to improve the availability of the medicine when the capsule isingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugars,such as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, andaliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt, and/oran absorption agent such as bentonite, kaolin, or dicalcium phosphate.The powder mixture can be granulated by wetting a binder such as syrup,starch paste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompound or salt of the present invention can also be combined with afree-flowing inert carrier and compressed into tablets directly withoutgoing through the granulating or slugging steps. A clear opaqueprotective coating consisting of a sealing coat of shellac, a coating ofsugar, or polymeric material, and a polish coating of wax can beprovided. Dyestuffs can be added to these coatings to distinguishdifferent dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of active ingredient. Syrups can be prepared by dissolving thecompound or salt thereof of the invention in a suitably flavouredaqueous solution, while elixirs are prepared through the use of anon-toxic alcoholic vehicle. Suspensions can be formulated by dispersingthe compound or salt of the invention in a non-toxic vehicle.Solubilizers and emulsifiers, such as ethoxylated isostearyl alcoholsand polyoxyethylene sorbitol ethers, preservatives, flavor additivessuch as peppermint oil, natural sweeteners, saccharin, or otherartificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred fordelivery of the pharmaceutical composition.

In accordance with another aspect of the invention there is provided aprocess for the preparation of a pharmaceutical composition comprisingmixing (or admixing) a compound of Formula (I) or salt thereof with atleast one excipient.

The present invention also provides a method of treatment in a mammal,especially a human. The compounds and compositions of the invention areused to treat cellular proliferation diseases. Disease states which canbe treated by the methods and compositions provided herein include, butare not limited to, cancer (further discussed below), autoimmunedisease, fungal disorders, arthritis, graft rejection, inflammatorybowel disease, proliferation induced after medical procedures,including, but not limited to, surgery, angioplasty, and the like. It isappreciated that in some cases the cells may not be in a hyper or hypoproliferation state (abnormal state) and still requires treatment. Forexample, during wound healing, the cells may be proliferating“normally”, but proliferation enhancement may be desired. Thus, in oneembodiment, the invention herein includes application to cells orindividuals afflicted or impending affliction with any one of thesedisorders or states.

The compositions and methods provided herein are particularly deemeduseful for the treatment of cancer including tumors such as prostate,breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.They are particularly useful in treating metastatic or malignant tumors.More particularly, cancers that may be treated by the compositions andmethods of the invention include, but are not limited to tumor typessuch as astrocytic, breast, cervical, colorectal, endometrial,esophageal, gastric, head and neck, hepatocellular, laryngeal, lung,oral, ovarian, prostate and thyroid carcinomas and sarcomas. Morespecifically, these compounds can be used to treat: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia (acute and chronic), acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one or related of theabove identified conditions.

The instant compounds can be combined with or co-administered with othertherapeutic agents, particularly agents that may enhance the activity ortime of disposition of the compounds. Combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and the use of at least one other treatment method. In oneembodiment, combination therapies according to the invention comprisethe administration of at least one compound of the invention andsurgical therapy. In one embodiment, combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and radiotherapy. In one embodiment, combination therapiesaccording to the invention comprise the administration of at least onecompound of the invention and at least one supportive care agent (e.g.,at least one anti-emetic agent). In one embodiment, combinationtherapies according to the present invention comprise the administrationof at least one compound of the invention and at least one otherchemotherapeutic agent. In one particular embodiment, the inventioncomprises the administration of at least one compound of the inventionand at least one anti-neoplastic agent. In yet another embodiment, theinvention comprises a therapeutic regimen where the EZH2 inhibitors ofthis disclosure are not in and of themselves active or significantlyactive, but when combined with another therapy, which may or may not beactive as a standalone therapy, the combination provides a usefultherapeutic outcome.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of an EZH2 inhibiting compound, as describedherein, and a further active ingredient or ingredients, known to beuseful in the treatment of cancer, including chemotherapy and radiationtreatment. The term further active ingredient or ingredients, as usedherein, includes any compound or therapeutic agent known to or thatdemonstrates advantageous properties when administered to a patient inneed of treatment for cancer. Preferably, if the administration is notsimultaneous, the compounds are administered in a close time proximityto each other. Furthermore, it does not matter if the compounds areadministered in the same dosage form, e.g. one compound may beadministered topically and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof specified cancers in the present invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology by V. T.Devita and S. Hellman (editors), 6th edition (February 15, 2001),Lippincott Williams & Wilkins Publishers. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to, anti-microtubule agents suchas diterpenoids and vinca alkaloids; platinum coordination complexes;alkylating agents such as nitrogen mustards, oxazaphosphorines,alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such asanthracycline, actinomycins and bleomycins; topoisomerase II inhibitorssuch as epipodophyllotoxins; antimetabolites such as purine andpyrimidine analogues and anti-folate compounds; topoisomerase Iinhibitors such as camptothecins; hormones and hormonal analogues; DNAmethyltransferase inhibitors such as azacitidine and decitabine; signaltransduction pathway inhibitors; non-receptor tyrosine kinaseangiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents;and cell cycle signaling inhibitors.

Typically, any chemotherapeutic agent that has activity against asusceptible neoplasm being treated may be utilized in combination withthe compounds the invention, provided that the particular agent isclinically compatible with therapy employing a compound of theinvention. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to: alkylating agents,anti-metabolites, antitumor antibiotics, antimitotic agents, nucleosideanalogues, topoisomerase I and II inhibitors, hormones and hormonalanalogues; retinoids, histone deacetylase inhibitors; signaltransduction pathway inhibitors including inhibitors of cell growth orgrowth factor function, angiogenesis inhibitors, and serine/threonine orother kinase inhibitors; cyclin dependent kinase inhibitors; antisensetherapies and immunotherapeutic agents, including monoclonals, vaccinesor other biological agents.

Nucleoside analogues are those compounds which are converted todeoxynucleotide triphosphates and incorporated into replicating DNA inplace of cytosine. DNA methyltransferases become covalently bound to themodified bases resulting in an inactive enzyme and reduced DNAmethylation. Examples of nucleoside analogues include azacitidine anddecitabine which are used for the treatment of myelodysplastic disorder.Histone deacetylase (HDAC) inhibitors include vorinostat, for thetreatment of cutaneous T-cell lymphoma. HDACs modify chromatin throughthe deactylation of histones. In addition, they have a variety ofsubstrates including numerous transcription factors and signalingmolecules. Other HDAC inhibitors are in development.

Signal transduction pathway inhibitors are those inhibitors which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation orsurvival. Signal transduction pathway inhibitors useful in the presentinvention include, but are not limited to, inhibitors of receptortyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domainblockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases,myoinositol signaling, and Ras oncogenes. Signal transduction pathwayinhibitors may be employed in combination with the compounds of theinvention in the compositions and methods described above.

Receptor kinase angiogenesis inhibitors may also find use in the presentinvention. Inhibitors of angiogenesis related to VEGFR and TIE-2 arediscussed above in regard to signal transduction inhibitors (both arereceptor tyrosine kinases). Other inhibitors may be used in combinationwith the compounds of the invention. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alpha_(v) beta₃) thatinhibit angiogenesis; endostatin and angiostatin (non-RTK) may alsoprove useful in combination with the compounds of the invention. Oneexample of a VEGFR antibody is bevacizumab (AVASTIN®).

Several inhibitors of growth factor receptors are under development andinclude ligand antagonists, antibodies, tyrosine kinase inhibitors,anti-sense oligonucleotides and aptamers. Any of these growth factorreceptor inhibitors may be employed in combination with the compounds ofthe invention in any of the compositions and methods/uses describedherein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibodyinhibitor of growth factor function. One example of an anti-erbB1antibody inhibitor of growth factor function is cetuximab (Erbittix™,C225). Bevacizumab (Avastin®) is an example of a monoclonal antibodydirected against VEGFR. Examples of small molecule inhibitors ofepidermal growth factor receptors include but are not limited tolapatinib (Tykerb™) and erlotinib)(TARCEVA®). Imatinib mesylate(GLEEVEC®) is one example of a PDGFR inhibitor. Examples of VEGFRinhibitors include pazopanib, ZD6474, AZD2171, PTK787, sunitinib andsorafenib.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem, Soc., 93:2325. 1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.lntem, Med., 111:273,1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p.16-23, 1995). Docetaxel,(2R,3S)—N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate2-benzoate, trihydrate; is commercially available as an injectablesolution as TAXOTERE®. Docetaxel is indicated for the treatment ofbreast cancer. Docetaxel is a semisynthetic derivative of paclitaxelq.v., prepared using a natural precursor, 10-deacetyl-baccatin III,extracted from the needle of the European Yew tree. The dose limitingtoxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate(NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine isindicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′], is commercially available asPARAPLATIN® as an injectable solution. Carboplatin is primarilyindicated in the first and second line treatment of advanced ovariancarcinoma. Bone marrow suppression is the dose limiting toxicity ofcarboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin, (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leucopenia tends to be more severethan thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′, 2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid, is commercially availableas methotrexate sodium. Methotrexate exhibits cell phase effectsspecifically at S-phase by inhibiting DNA synthesis, repair and/orreplication through the inhibition of dyhydrofolic acid reductase whichis required for synthesis of purine nucleotides and thymidylate.Methotrexate is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of choriocarcinoma, meningealleukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head,neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia,and anemia) and mucositis are expected side effect of methotrexateadministration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I—DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I—DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer. The doselimiting side effect of topotecan HCl is myelosuppression, primarilyneutropenia.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalcompositions may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage compositions are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical compositions may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such compositions maybe prepared by any method known in the art of pharmacy, for example bybringing into association a compound of formal (I) with the carrier(s)or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by tablet forming dies by means ofthe addition of stearic acid, a stearate salt, talc or mineral oil. Thelubricated mixture is then compressed into tablets. The compounds of thepresent invention can also be combined with a free flowing inert carrierand compressed into tablets directly without going through thegranulating or slugging steps. A clear or opaque protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of a compound of formula (I). Syrups can be prepared bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit pharmaceutical compositions for oraladministration can be microencapsulated. The formulation can also beprepared to prolong or sustain the release as for example by coating orembedding particulate material in polymers, wax or the like.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe composition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The pharmaceutical compositions may bepresented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the pharmaceutical compositions may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the intended recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant prescribing the medication. However, an effective amountof a compound of formula (I) for the treatment of anemia will generallybe in the range of 0.001 to 100 mg/kg body weight of recipient per day,suitably in the range of 0.01 to 10 mg/kg body weight per day. For a 70kg adult mammal, the actual amount per day would suitably be from 7 to700 mg and this amount may be given in a single dose per day or in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a salt orsolvate, etc., may be determined as a proportion of the effective amountof the compound of formula (I) per se. It is envisaged that similardosages would be appropriate for treatment of the other conditionsreferred to above.

DEFINITIONS

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein, the term “alkyl” represents a saturated, straight, orbranched hydrocarbon moiety, preferably having from one to twelve carbonatoms. The term “(C₁-C₆)alkyl” refers to an alkyl moiety containing from1 to 6 carbon atoms. Exemplary alkyls include, but are not limited tomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,pentyl, and hexyl.

As used herein, the term “haloalkyl” refers to an alkyl group, definedhereinabove, substituted with one or more halo substituents.

The term “alkylthio” as used herein is meant S(C₁-C₈alkyl) including—SCH₃, —SCH₂CH₃ and the like per the definition of alkyl above.

The term “acyloxy” means —OC(O)C₁-C₈alkyl and the like per thedefinition of alkyl above.

“Acylamino” means —N(H)C(O)C₁C₈alkyl and the like per the definition ofalkyl above.

“Aryloxy” means —O(aryl), —O(substituted aryl), —O(heteroaryl) or—O(substituted heteroaryl).

“Acylamino” means —NH(aryl), —NH(substituted aryl), —NH(heteroaryl) or—NH(substituted heteroaryl), and the like.

When the term “alkenyl” (or “alkenylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon double bonds. Examplesinclude ethenyl (or ethenylene) and propenyl (or propenylene).

When the term “alkynyl” (or “alkynylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon triple bonds. Examplesinclude ethynyl (or ethynylene) and propynyl (or propynylene).

The term “C₅-C₈cycloalkenyl” refers to a non-aromatic monocycliccarboxycyclic ring having the specified number of carbon atoms and up to3 carbon-carbon double bonds. “Cycloalkenyl” includes by way of examplecyclopentenyl and cyclohexenyl.

As used herein, the term “hydroxylalkyl” refers to an alkyl group,defined hereinabove, substituted preferably with 1, 2 or 3 hydroxylsubstituents.

As used herein, the term “cycloalkyl” refers to an unsubstituted orsubstituted mono- or polycyclic non-aromatic saturated ring, whichoptionally includes an alkylene linker through which the cycloalkyl maybe attached. Exemplary “cycloalkyl” groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andthe like, as well as unsubstituted and substituted versions thereof.

As used herein, the term “bicycloalkyl” refers to two cycloalkyl groups,defined hereinabove, connecting with each other to form a bridged, fusedor spiro bicycle compound. Representative bicycloalkyl groups include,not limited to, spiro[4.4] nonance, bicyclo[3.1.1]heptanes andbicyclo[3.2.0]heptanes

As used herein, the term “alkoxy” refers to the group —OR^(a), whereR^(a) is alkyl or cycloalkyl as defined above.

The terms “halogen” and “halo” represent chloro, fluoro, bromo, or iodosubstituents. “Hydroxy” or “hydroxyl” is intended to mean the radical—OH.

“Heterocycloalkyl” represents a group or moiety comprising anon-aromatic, monovalent monocyclic or bicyclic radical, which issaturated or partially unsaturated, containing 3 to 10 ring atoms, whichincludes 1 to 3 heteroatoms independently selected from nitrogen, oxygenand sulfur, including N-oxides, sulfur oxides, and dioxides.Illustrative examples of heterocycloalkyls useful in the presentinvention include, but are not limited to, azetidinyl, pyrrolidinyl,pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl,thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,hexahydro-1H-1,4-diazepinyl, azabicylo [3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo [4.3.0]nonyl, oxabicylo[2.2.1]heptyl,1,1-dioxidotetrahydro-2H-thiopyranyl and 1,5,9-triazacyclododecyl.

The term “aryl” refers to a carbocyclic aromatic moiety (such as phenylor naphthyl) containing the specified number of carbon atoms,particularly from 6-10 carbon atoms. Examples of aryl radicals include,but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl,anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyland the like. Unless otherwise indicated, the term “aryl” also includeseach possible positional isomer of an aromatic hydrocarbon radical, suchas in 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl,6-tetrahydronaphthyl, 1-phenanthridinyl, 2-phenanthridinyl,3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl,8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.

As used herein, the term “heteroaryl”, unless otherwise defined, ismeant an aromatic ring system containing carbon(s) and at least oneheteroatom. Heteroaryl may be monocyclic or polycyclic, substituted orunsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatomsin the ring, while a polycyclic heteroaryl may contain 1 to 8 heteroatoms. A polycyclic heteroaryl ring may contain fused, spiro or bridgedring junctions, for example, bicyclic heteroaryl is a polycyclicheteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 memberatoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms(carbons and heteroatoms). Exemplary 5- to 6-memebered heteroarylsinclude, but are not limited to, furanyl, thiophenyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-traizolyl, oxazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiadiazolyl, isothiazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, andtriazinyl. Other exemplary heteroaryl groups include, but are notlimited to benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl,1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl,indolyl, isoindolyl, indolinyl, isoindolinyl, benzimidazolyl,dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl,benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl,pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl,imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl,purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Suitablesubstituents for heteroaryl are described in the definition of“optionally substituted.”

As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “acetyl” refers to the group —C(═O)R^(b), whereR^(b) is alkyl, cycloalkyl, or heterocyclyl, as each is defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and event(s) that do not occur.

As used herein, unless otherwise defined, the phrase “optionallysubstituted” or variations thereof denote an optional substitution,including multiple degrees of substitution, with one or moresubstitutent group. The phrase should not be interpreted as duplicativeof the substitutions herein described and depicted. Exemplary optionalsubstituent groups include acyl, alkyl, alkylsulfonyl, alkoxy,alkoxycarbonyl, cyano, halogen, haloalkyl, hydroxyl, oxo, and nitro.

As used herein, the term “treatment” includes prophylaxis and refers toalleviating the specified condition, eliminating or reducing one or moresymptoms of the condition, slowing or eliminating the progression of thecondition, and preventing or delaying the reoccurrence of the conditionin a previously afflicted or diagnosed patient or subject. Prophylaxis(or prevention or delay of disease onset) is typically accomplished byadministering a drug in the same or similar manner as one would to apatient with the developed disease or condition.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function. Foruse in therapy, therapeutically effective amounts of a compound ofFormula (I), as well as salts thereof, may be administered as the rawchemical. Additionally, the active ingredient may be presented as apharmaceutical composition.

Compound Preparation

Abbreviations

-   AcOH acetic acid-   AIBN azobisisobutyronitrile-   AlCl₃ aluminum trichloride-   aq. aqueous-   Ar argon gas-   Br₂ bromine-   CBr₄ carbon tetrabromide-   CCl₄ carbon tetrachloride-   CH₂Cl₂ dichloromethane-   CH₃CN acetonitrile-   CH₃I methyl iodide-   (CH₂O)_(n) paraformaldehyde-   CH₃SO₃H methanesulfonic acid-   conc. Concentrated-   Cs₂CO₃ cesium carbonate-   CuBr copper(I) bromide-   CuCN copper(I) cyanide-   CuI copper(I) iodide-   (COCl)₂ oxalyl chloride-   DCM dichloromethane-   DCE 1,2-dichloroethane-   DEAD Diethyl Azodicarboxylate-   DIPEA N,N-diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DME 1,2-dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   EA ethyl acetate-   EtOAc ethyl acetate-   EDC N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   Et₃N triethylamine-   Et₂O diethyl ether-   EtOH ethanol-   FeSO₄ iron(II) sulfate-   h hour(s)-   H₂ hydrogen gas-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBr hydrobromic acid-   HCl hydrochloric acid-   H₂O water-   HNO₃ nitric acid-   HOBt hydroxybenzotriazole-   HPLC high-performance liquid chromatography-   H₂SO₄ sulfuric acid-   I₂ iodine-   i-PrMgCl isopropylmagnesium chloride-   K₂CO₃ potassium carbonate-   K₃Fe(CN)₆ potassium ferricyanide-   KOt-Bu potassium tert-butoxide-   K₃PO₄ potassium phosphate tribasic-   LCMS liquid chromatography mass spectrometry-   LiAlH₄ lithium aluminum hydride-   LiOH lithium hydroxide-   m-CPBA meta-chloroperbenzoic acid-   MeMgBr methyl magnesium bromide-   MeOH methanol-   Mg magnesium-   MgCl₂ magnesium chloride-   min minute(s)-   MnO₂ manganese dioxide-   N₂ nitrogen gas-   NaBH₄ sodium borohydride-   NaCN sodium cyanide-   Na₂CO₃ sodium carbonate-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   NaHSO₃ sodium bisulfite-   NaN₃ sodium azide-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NBS N-Bromosuccinimide-   n-BuLi n-butyllithium-   NH₄Cl ammonium chloride-   NMM N-methylmorpholine-   PCC pyridinium chlorochromate-   PE petroleum ether-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   PhNO₂ nitrobenzene-   POCl₃ phosphoryl chloride-   PPh₃ triphenylphosphine-   p-TsOH para-toluene sulfonic acid-   R_(f) retention factor-   rt room temperature-   R_(t) retention time-   SOCl₂ thionyl chloride-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   TLC thin layer chromatography-   ®T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane    2,4,6-trioxide-   Zn zinc powder    Generic Synthesis Schemes

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working examples. The skilled artisan willappreciate that if a substituent described herein is not compatible withthe synthetic methods described herein, the substituent may be protectedwith a suitable protecting group that is stable to the reactionconditions. The protecting group may be removed at a suitable point inthe reaction sequence to provide a desired intermediate or targetcompound. In all of the schemes described below, protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts, (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of the present invention. Starting materials are commerciallyavailable or are made from commercially available starting materialsusing methods known to those skilled in the art.

The following guidelines apply to all experimental procedures describedherein. All reactions were conducted under a positive pressure ofnitrogen using oven-dried glassware, unless otherwise indicated.Temperatures designated are external (i.e. bath temperatures), and areapproximate. Air and moisture-sensitive liquids were transferred viasyringe. Reagents were used as received. Solvents utilized were thoselisted as “anhydrous” by vendors. Molarities listed for reagents insolutions are approximate, and were used without prior titration againsta corresponding standard. All reactions were agitated by stir bar,unless otherwise indicated. Heating was conducted using heating bathscontaining silicon oil, unless otherwise indicated. Reactions conductedby microwave irradiation (0-400 W at 2.45 GHz) were done so using aBiotage Initiator™ 2.0 instrument with Biotage microwave EXP vials(0.2-20 mL) and septa and caps. Irradiation levels utilized (i.e. high,normal, low) based on solvent and ionic charge were based on vendorspecifications. Cooling to temperatures below −70° C. was conductedusing dry ice/acetone or dry ice/2-propanol. Magnesium sulfate andsodium sulfate used as drying agents were of anhydrous grade, and wereused interchangeably. Solvents described as being removed “in vacuo” or“under reduced pressure” were done so by rotary evaporation.

Preparative normal phase silica gel chromatography was carried out usingeither a Teledyne ISCO CombiFlash Companion instrument with RediSep orISCO Gold silica gel cartridges (4 g-330 g), or an Analogix IF280instrument with SF25 silica gel cartridges (4 g-3-00 g), or a BiotageSP1 instrument with HP silica gel cartridges (10 g-100 g). Purificationby reverse phase HPLC was conducted using a YMC-pack column (ODS-A75×30mm) as solid phase, unless otherwise noted. A mobile phase of 25mL/min A (acetonitrile-0.1%TFA) : B (water-0.1% TFA), 10-80% gradient A(10 min) was utilized with UV detection at 214 nM, unless otherwisenoted.

A PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex,Thornhill, Ontario, Canada) was operated using electrospray ionizationin the positive ion detection mode. The nebulizing gas was generatedfrom a zero air generator (Balston Inc., Haverhill, Mass., USA) anddelivered at 65 psi and the curtain gas was high purity nitrogendelivered from a Dewar liquid nitrogen vessel at 50 psi. The voltageapplied to the electrospray needle was 4.8 kV. The orifice was set at 25V and mass spectrometer was scanned at a rate of 0.5 scan/sec using astep mass of 0.2 amu and collecting profile data.

Method A LCMS. Samples were introduced into the mass spectrometer usinga CTC PAL autosampler (LEAP Technologies, Carrboro, NC) equipped with ahamilton 10 uL syringe which performed the injection into a Valco10-port injection valve. The HPLC pump was a Shimadzu LC-10ADvp(Shimadzu Scientific Instruments, Columbia, Md.) operated at 0.3 mL/minand a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold.The mobile phase was composed of 100% (H₂O 0.02% TFA) in vessel A and100% (CH₃CN 0.018% TFA) in vessel B. The stationary phase is Aquasil(C18) and the column dimensions were 1 mm×40 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method B, LCMS. Alternatively, an Agilent 1100 analytical HPLC systemwith an LC/MS was used and operated at 1 mL/min and a linear gradient 5%A to 100% B in 2.2 min with a 0.4 min hold. The mobile phase wascomposed of 100% (H₂O 0.02% TFA) in vessel A and 100% (CH₃CN 0.018% TFA)in vessel B. The stationary phase was Zobax (C₈) with a 3.5 um particalsize and the column dimensions were 2.1 mm×50 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method C, LCMS. Alternatively, an MDSSCIEX API 2000 equipped with acapillary column of (50×4.6 mm, 5 μm) was used. HPLC was done onAgilent-1200 series UPLC system equipped with column Zorbax SB-C18(50×4.6 mm, 1.8 μm) eluting with CH₃CN: ammonium acetate buffer. Thereactions were performed in the microwave (CEM, Discover).

¹H-NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHzinstrument, with ACD Spect manager v. 10 used for reprocessing.Multiplicities indicated are: s=singlet, d=doublet, t=triplet,q=quartet, quint=quintet, sxt=sextet, m=multiplet, dd=doublet ofdoublets, dt=doublet of triplets etc. and br indicates a broad signal.All NMRs in DMSO unless otherwise noted.

Analytical HPLC: Products were analyzed by Agilent 1100 AnalyticalChromatography system, with 4.5×75 mm Zorbax XDB-C₁₈ column (3.5 um) at2 mL/min with a 4 min gradient from 5% CH₃CN (0.1% formic acid) to 95%CH₃CN (0.1% formic acid) in H₂O (0.1% formic acid) and a 1 min hold.

The compounds of formula (I) can be made according to Scheme 1 oranalogous methods. Reductive amination of compound (1) afforded thevarious amine analogs (2), which was hydrolyzed under NaOH to makecarboxylic acid compound (3). Amide formation between compound (3) andintermediate (4) under EDC and HOAT afforded compound (5), whichunderwent Suzuki coupling to afford the example compounds (6).

Alternatively, Examples can be made following Scheme 2. Compound (7) canbe made from compound (1) under Sandmeyer reaction condition. Compound(7) underwent substitution and hydrolysis to afford compound (8), whichwas coupled with compound (4) under EDC and HOAT to form compound (9).Example compound (10) can be obtained by Suzuki reaction of compound (9)with corresponding boric acid.

Preparation of Intermediates

Intermediate 1 3-(Aminomethyl)-4,6-dimethyl-2(1H)-pyridinonehydrochloride

Palladium on carbon (10%) (3.24 g) was charged into a 2 L dry Parrbottle and a small amount of acetic acid was added. Next added4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (30 g, 202.7mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g),and acetic acid (1 L). The bottle was capped, placed on Parr apparatus,and shaken under an atmosphere of H2 (100 psi) for 2 days. The reactionmixture was filtered. The solvent was removed to give a residue, whichwas treated with 150 mL of conc. HCl, and the formed solids werefiltered. The yellow filtrate was concentrated. To the crude compoundwas added 30 mL of conc. HCl and 150 mL EtOH, the contents cooled to 0°C., and stirred at 0° C. for 2h. The formed solids were filtered, washedwith cold EtOH, ether, and dried. The product was collected as 36 g.This batch was combined with other batches prepared on smaller scalesand triturated with ether to give 51 g of pure compound. 1H NMR (400MHz, DMSO-d6) δ ppm 11.85 (br s,1 H) 8.13 (br s, 3 H) 5.93-6.01 (m, 1 H)3.72-3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).

Intermediate 23-(Aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone

To a dried 500 mL Parr bottle equipped with nitrogen inlet were addedsodium acetate (1.502 g, 18.30 mmol), 10% palladium on carbon (1.579 g,0.742 mmol), platinum(IV) oxide (0.011 g, 0.049 mmol) and a small amountof acetic acid to wet the catalysts, under nitrogen stream. Next wasadded 2-hydroxy-6-methyl-4-(trifluoromethyl)-3-pyridinecarbonitrile (2.0g, 9.89 mmol) followed by acetic acid (175 mL) while under nitrogenatmosphere. The contents were sealed, placed on a Parr shaker, andreacted at 40 psi of H₂ for ca. 6 hr, keeping the H₂ psi between 20 and40 psi (vessel was refilled twice). The vessel was purged with nitrogenand the reaction mixture filtered through Celite, and the filter pad wasfurther washed with a small amount of acetic acid. The volatiles wereremoved in vacuo to afford a residue, which was dried under high vacuumfor 45 min The solid was suspended in conc. HCl (12 mL), stirred, andfiltered. The clear filtrate was concentrated in vacuo and the residuedried under high vacuum. The collected solid was suspended in conc. HCl(2 mL) and diluted with EtOH (13 mL). The contents were agitated andstored at ca. 0° C. (freezer) for 30 min to give a white solid. Thesolid was filtered and washed with cold ethanol (5 mL). The solid wasfiltered and dried in vacuum oven for 1 h to give3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone (0.95 g,40%). LCMS E-S (M+H)=206.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H), 3.40-3.62 (m, 2 H), 3.87 (d, J=5.05 Hz, 2 H), 8.12-8.37 (m, 3 H).

Intermediate 3 3-(Aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone

3a) 4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a stirred suspension of CrCl₂ (58 g, 472.8 mmol) in THF (1500 mL) wasadded a THF solution (500 mL) of 1,1-dichloro-2-propanone(10 g, 78.8mmol) and cyclohexanecarbaldehyde (8.84 g, 78.8 mmol). The reactionmixture was heated at reflux for 2 h, and then quenched by the additionof 1.0 M HCl. The reaction mixture was filtered through a pad of Celiteand concentrated in vacuo. The crude residue (10 g) was added to asolution of DMSO (150 mL) containing t-BuOK (7.5 g, 65.7 mmol) andcyanoacetamide (6.1 g, 72.3 mmol) and stirred at room temperature for 30min Additional t-BuOK (22.5 g, 197.1 mmol) was added and the reactionmixture was stirred under an atmosphere of oxygen for an additional 1 h.The contents were purged with argon, diluted with 4 volumes of H₂O, andthen 5 volumes of 4 N HCl, which were added slowly. The reaction mixturewas filtered, washed with water and dried to give4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4.5 g,32%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.25 (s, 1H), 2.61-2.65 (m, 1H),2.22 (s, 3H), 1.66-1.79 (m, 4H), 1.24-1.46 (m, 6H).

3b) 3-(Aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone

To an ice-bath cooled THF (100 mL) solution of the product from step 1(2 g, 9.26 mmol) was added NaBH₄ (0.81 g, 21.3 mmol) and 12 (2.3 g, 9.26mmol), and the mixture stirred for 30 min The reaction mixture was thenheated at reflux for 3 h, and then allowed to cool to room temperature.After cooling to 0° C., the reaction mixture was acidified by slowaddition of 3 N HCl (1 mL). The reaction mixture was concentrated invacuo and the crude product purified by reverse phase HPLC to give3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone as a solid (0.5g, 25%). LCMS E-S (M+H)=221.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.8-11.9(br s, 1H), 7.80-7.93 (br s, 3H), 6.07 (s, 1H), 3.69 (s, 2H), 2.67-2.75(m, 1H), 2.17 (s, 3H), 1.58-1.72 (m, 5H), 1.19-1.41 (m, 5H).

Intermediate 4 3-(Aminomethyl)-4-cyclopropyl-6-methyl-2(1H)-pyridinone

The title compound was prepared in the same manner as described for3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3)using 4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5g, 28.7 mmol). Obtained: 0.50 g (10%). LCMS E-S (M+H)=179.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.76-11.78 (br s, 1H), 7.82-7.92 (br s, 3H), 5.61(s, 1H), 3.94-3.99 (m, 2H), 2.11 (s, 3H), 1.98-2.05 (m, 1H), 0.95-1.01(m, 2H), 0.74-0.79 (m, 2H).

Intermediate 5 3-(Aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone

5a) 6-Methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile

To a solution of DMSO (300 mL) containing t-BuOK (20 g, 178 mmol) andcyanoacetamide (16.5 g, 196 mmol) was added (3E)-3-hepten-2-one (20 g,178 mmol), and the contents were stirred at room temperature for 30 minAdditional t-BuOK (60 g, 534 mmol) was added and the reaction mixturewas placed under an atmosphere of oxygen for an additional 1 h. Thereaction mixture was purged with argon, diluted with 4 volumes of H₂O,and then 5 volumes of 4 N HCl, which were added slowly. The reactionmixture was filtered, washed with water, and dried to give6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (10 g, 32%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.25-12.40 (br s, 1H), 6.18 (s, 1H),2.53 (t, 2H), 2.22 (s, 3H), 1.57-1.64 (m, 2H), 0.84 (t, 3H).

5b) 3-(Aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone

The title compound was prepared in the same manner as described for3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3)using 6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (2 g,11.2 mmol). Obtained: 1.2 g (60%). LCMS E-S (M+H)=181.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.85-7.95 (br s, 3H), 5.99 (s, 1H), 3.80-3.85 (m,2H), 2.42 (t, 2H), 2.14 (s, 3H), 1.43-1.49 (m, 2H), 0.86 (t, 3H).

Intermediate 6 3-(Aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone

The title compound was prepared in the same manner as described for3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5)using (3E)-4-phenyl-3-buten-2-one (20 g, 137 mmol). LCMS E-S(M+H)=215.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.2-12.3 (br s, 1H),7.88-8.00 (br s, 3H), 7.43-7.51 (m, 3H), 7.29-7.38 (m, 2H), 6.08 (s,1H), 3.67-3.70 (m, 2H), 2.23 (s, 3H).

Intermediate 73-(Aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone

The title compound was prepared in the same manner as described for3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5)using (3E)-5-methyl-3-hexen-2-one (20 g, 137 mmol). LCMS E-S(M+H)=181.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.8-11.9 (br s, 1H),7.86-7.96 (br s, 3H), 6.10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m,1H), 2.17 (s, 3H), 1.08 (d, 6H).

Intermediate 8 3-(Aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone

8a) 4-Methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile

To a solution of NaNH₂ (32.5 g, 862 mmol) in anhydrous ether (500 mL) at30° C. was added dropwise a mixture of butyric acid ethyl ester (50 g,431 mmol) and acetone (37.5 g, 646.5 mol). After addition, the reactionmixture was stirred for 4 h. The reaction mixture was poured onto icewater with stirring. Additional ether was added, and the layers wereseparated. The aqueous layer was acidified to pH 5.0 with 2 N HCl andthen to pH 7.5 with Na₂CO₃. The aqueous layer was then extracted withether. The combined organic layers were dried over Na₂SOl₄, filtered,and concentrated in vacuo. The crude product, 2,4-heptanedione (20 g,156 mmol), and 2-cyanoacetamide (13.12 g, 156 mmol) were suspended inEtOH (160 mL) at 75° C., followed by addition of piperidine (13.2 g, 156mmol). The contents were stirred and heated at reflux for 1 h. Themixture was cooled to room temperature and filtered. The collected solidwas suspended in water and stirred for 1 h. The mixture was filtered anddried to give 4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile(11 g, 40%). LCMS E-S (M+H)=181.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.3-12.4 (br s, 1H), 6.25 (s, 1H), 3.64 (s, 3H), 2.50 (t, 2H), 1.63 (m,2H), 0.94 (t, 3H).

8b) 3-(Aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone

Sodium acetate (3.5 g, 42.6 mmol), palladium on carbon (0.81 g) andplatinum oxide (0.1 g) were placed in a dried Parr bottle flushed withnitrogen, followed by addition of a small amount of acetic acid (to wetthe catalysts). A solution of4-methyl-2-oxo-6-propyl-1,2-dihydro-pyridine-3-carbonitrile (5 g, 28mmol) in acetic acid was added to the Parr bottle followed by additionalacetic acid (200 mL). The vessel was capped, placed on Parr apparatusand hydrogenated at 45 psi for 12 h. The reaction mixture was filteredand the filtrate concentrated in vacuo. The crude product was purifiedby preparative HPLC to afford the title compound (TFA salt) as 4.1 g(87%). LCMS E-S (M+H))=181.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.8-11.9(br s, 1H), 7.83-7.88 (br s, 3H), 5.99 (s, 1H), 3.77-3.81 (m, 2H), 2.37(t, 2H), 1.53 (m, 2H), 0.83 (t, 3H).

Intermediate 9 3-(Aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinonehydrochloride

9a) 1-Cyclopropyl-1,3-butanedione

To a stirring solution of THF (100 mL) was added potassium tert-butoxide(5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone(3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at35° C., via addition funnel over a 25 min period. The contents wereheated and stirred at 60° C. After 3 h, the contents were removed fromheating, and allowed to cool to room temperature. The reaction mixturewas carefully diluted with 30 mL 2 N HCl and stirred for 10 min Themixture was extracted with diethyl ether (3×50 mL), and the combinedorganic layers washed with brine (1×50 mL). The organic layer was driedover MgSOl₄, filtered, and concentrated in vacuo. Purification bychromatography on silica gel (eluent: 0 to 15% EtOAc in hexanes) withgood separation afforded 1-cyclopropyl-1,3-butanedione as a light yellowcolored oil, 3.9 g in ˜75% purity (residual solvent), for an overallyield of 70%. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.89-0.96 (m, 2 H),1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1 H),15.5-16.0 (br s, 1H).

9b) 6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a stirred solution of ethanol (5 mL) were added1-cyclopropyl-1,3-butanedione (505 mg, 3.00 mmol) and cyanoacetamide(252 mg, 3.00 mmol), and the heterogenous contents heated untilhomogenous (ca. 75° C.). Piperidine was added (0.395 mL, 4.00 mmol) andthe mixture was heated at reflux for 30 min The reaction mixture wasallowed to cool to room temperature, wherein precipitation ensued. Thesolid precipitate was filtered and set aside. The filtrate wasconcentrated in vacuo and the oily residue treated with minimal EtOAcand then 10 mL hexanes to afford a second crop of solid. The solidproduct crops were combined, suspended in water (7 mL), vigorouslystirred, and vacuum filtered to afford6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as anearly white solid (380 mg, 73%). LCMS E-S (M+H)=175.1. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.01-1.09 (m, 2 H), 1.28 (dd, J=8.59, 2.27 Hz, 2 H),1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1 H).

9c) 1,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate

6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.35 g,2.01 mmol) was added to methanol (20 mL) and the stirred contents cooledto −10° C. Next was added di-tert-butyloxycarbonyl (0.933 mL, 4.02 mmol)and the suspension stirred for 15 min Next was added in NiCl₂-6H₂O(0.055 g, 0.201 mmol) as a solid and stirred for 5 min Then NaBH₄ (0.532g, 14.06 mmol) was added in 6 portions with 5 min increments betweeneach portion. Then the ice bath was removed and the contents werestirred with warming to room temperature overnight. The reaction mixturewas returned to −10° C., followed by addition of 3 more portions ofNaBH₄ (0.532 g, 14.06 mmol). The ice bath was removed and the mixturestirred at room temperature for 1 h. The contents were quenched byaddition of diethylethylene amine (0.218 mL, 2.01 mmol) and stirred for45 min at room temperature. The volatiles were removed in vacuo and theresidue suspended in EtOAc and saturated NaHCO₃. The organic layer waswashed with additional NaHCO₃. The layers were separated, and theorganic layer dried over MgSOl₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography (eluent: 10%methanol in dichloromethane). The collected product was dried underhi-vacuum for 1 h, and then treated with ether and filtered. Afterdrying in vacuum oven at 45° C. for 2 h,1,1-dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamatewas collected (0.28 g, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.80(m, 2 H), 0.88-0.96 (m, 2 H), 1.36 (s, 9 H), 1.70-1.82 (m, 1 H), 2.11(s, 3 H), 3.95 (d, J=5.31 Hz, 2 H), 5.66 (s, 1 H), 6.51 (t, J=4.80 Hz, 1H) ,11.50 (br. s., 1 H).

9d) 3-(Aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinonehydrochloride

1,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate(0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL).The suspension was stirred at room temperature for 5 min, followed byaddition of 4 M HCl in dioxane (5.03 mL, 20.12 mmol), and the contentswere stirred at room temperature overnight. The volatiles were thenremoved in vacuo to afford a solid. The solid was triturated with ether,filtered, and dried in a vacuum oven at 45° C. for 4 h. The titlecompound was collected (0.22 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 0.78-0.86 (m, 2 H), 0.95-1.03 (m, 2 H), 1.83 (tt, J=8.46, 5.05 Hz, 1H), 2.16-2.22 (m, 3 H), 3.75 (q, J=5.47 Hz, 2 H), 5.79 (s, 1 H), 8.02(br. s., 3 H), 11.92 (br. s., 1 H).

Intermediate 10 3-(Aminomethyl)-4-ethyl-6-methyl-2(1H)-pyridinonehydrochloride

10a) Hex-3-en-2-one

To a stirred solution of 1-(triphenylphosphoranylidene)-2-propanone (100g, 307 mmol) in DCM (500 mL) was added propionaldehyde (140 mL, 1929mmol) at room temperature. The reaction mixture was then stirred at roomtemperature for 18 hours. The reaction was monitored by TLC. The solvent(DCM) was distilled off using ordinary distillation. The residue wasthen distilled using fractional distillation under vacuum (˜450 mbar)and the desired product was isolated. The title compound, hex-3-en-2-one(20 g, 66%), was collected at 110° C. ¹H NMR (CDCl₃, 400 MHz) δ ppm1.071-1.121 (t, 3H, J=7.4 Hz), 2.250-2.299 (m, 5H), 6.054-6.094 (d, 1H,J=16Hz), 6.823-6.895 (m, 1H).

10b) 4-Ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile

To a stirred solution of t-BuOK (22.85 g, 204.08 mmol) andcyanoacetamide (18.8 g, 224.1 mmol) in DMSO (300 mL) was addedhex-3-en-2-one (20 g, 204.08 mmol) under argon atmosphere at roomtemperature. The reaction mixture was then stirred at room temperaturefor 30 min and then added additional t-BuOK (68.5 g, 612.05 mmol) wasadded. Argon gas was displaced by oxygen gas and the mixture stirred for48 hrs at room temperature in presence of oxygen. Reaction was monitoredby TLC. The reaction mixture was cooled to 0° C. and diluted with water(100 mL) followed by 4 N HCl (120 mL). The mixture was stirred for 15min and the resulting solid was filtered. The solid was washed withwater (1 L) and dried to afford the title compound,4-ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (10.5 g, 31%),as an off white solid. ¹H NMR (CDCl₃, 400 MHz) : δ ppm 1.148-1.185 (t,3H, J=7.4 Hz), 2.237 (s, 3H), 2.557-2.614(m, 2H), 6.211 (s, 1H), 12.330(broad s, 1H). MS(ES) [M+H]⁺ 161.06.

10c) 3-(Amino methyl)-4-ethyl-6-methylpyridin-2(1H)-one

To a suspension of Raney Nickel (6 g) in methanol (200 mL) was added4-ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (10 g, 61.7mmol) and methanolic ammonia (750 mL). The reaction mixture was stirredat room temperature under hydrogen pressure (80 psi) for 48 hrs. Thereaction mixture was filtered through Celite and washed with methanol(250 mL). The filtrate was concentrated under reduced pressure and theresidue purified by filter column using silica gel (60-120 mesh), elutedwith 10% MeOH in CHCl₃, to afford 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (5.6 g, 54%) as an off whitesolid. ¹H NMR (DMSO-D₆, 400 MHz) (free amine): δ ppm 1.063-1.101 (t, 3H,J=7.6 Hz), 2.101 (s, 3H), 2.412-2.449 (m, 2H), 3.448 (s, 2H), 5.835(s,1H). MS(ES) [M+H]⁺ 167.06.

10d) 3-(Aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one hydrochloride

3-(Amino methyl)-4-ethyl-6-methylpyridin-2(1H)-one, (5.6 g, 33 mmol) wassuspended in DCM (560 mL) and the insoluble contents/particles werefiltered. The filtrate was concentrated and dried. The residue wasdissolved in DCM (10 mL) and 4 M HCl in 1,4-dioxane (16 mL, 66 mmol) wasadded at 0° C. and stirred for 10 min, at which time the reactionmixture was concentrated under high-vacuum and dried. The resultingcrude solid was triturated with hexane (150 mL) and filtered. The solidwas dried under vacuum. Collected 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one hydrochloride (5.9 g, 86%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.082-1.120 (t, 3H, J=7.6 Hz), 2.179 (s,3H), 2.503-2.544 (m, 2H), 3.785-3.798 (d, 2H, J=5.2 Hz), 6.024(s,1H),7.985 (broad s,2H), 11.858 (broad s,1H). MS(ES) [M+H]⁺ 167.2.

Intermediate 11 3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone

11a) 4-ethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a solution of t-BuOK (17.2 g, 153 mmol) and cyanoacetamide (13 g, 153mmol) in CH₃CN (225 mL) was added (3E)-3-hexen-2-one (15 g, 153 mmol) atroom temperature under N₂ atmosphere. The reaction mixture was stirredfor 30 min To the reaction mixture was added additional t-BuOK (51.4 g),and the N2 was displaced by oxygen. After stirring for 1 h withoutexternal cooling, the mixture was diluted with 4 N HCl, which was addedslowly and with good stirring. The mixture was filtered, washed withEtOH, dried to give6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g, 21%). ¹HNMR (400 MHz, DMSO-d₆) δ 12.33 (br. s., 1H), 6.18 (s, 1H), 2.45 (q, 2H),2.30 (s, 3H), 1.11 (t, 3H).

11b) 3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone

To an ice bath cooled THF solution (200 mL) of6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (7 g, 43.2mmol) was added NaBH₄ (4.2 g, 108 mmol), and I₂ (11.2 g, 43.2 mmol), andthe contents were stirred for 30 min The reaction mixture was thenheated at reflux overnight. The reaction mixture was cooled, andcarefully neutralized by slow addition of 4 N HCl at 0° C. The mixturewas dried over MgSOl₄, filtered, and concentrated in vacuo. The productwas purified by HPLC to give3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone as a TFA salt (1.9 g,26.4%). LCMS MH+=167.1 ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (br. s., 1H),7.82 (br s, 3H), 5.97 (s, 1H), 3.75-3.77 (m, 2H), 2.39 (q, 2H), 2.17 (s,3H), 1.09 (t, 3H).

Intermediate 12 3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one

12a) (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one

To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) andacetone (34.58 g, 595 mmol) in THF (150 mL) was slowly added NaOMe(12.87 g, 238 mmol) at 35-40° C. The mixture was stirred at roomtemperature for 0.5 h, and then heated at reflux for 3 h. The mixturewas cooled to room temperature and filtered to give a solid, which waswashed with t-BuOMe, and dissolved in H₂O. The solution was acidifiedwith acetic acid and the resulting oily product was extracted withCHCl₃. The solvent was removed in vacuo, and the crude product wasobtained (12 g, 37%) and used without further purification. ¹H NMR (400MHz, DMSO-d₆) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H), 2.21 (s, 3H);note: enolic OH does not appear.

12b) 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile and4-methyl-6-oxo-1,6-dihydro-2,4′-bipyridine-5-carbonitrile

To a solution of (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one (8 g,crude, 49 mmol) and cyanoacetamide (4.12 g, 49 mmol) in anhydrous EtOH(100 mL) was added piperidine (4.17 g, 49 mmol) under N2 at 75° C. Themixture was heated at reflux for 1 h, and then cooled to roomtemperature. After filtration, the solid was collected and washed withH₂O to give the crude product (4 g) as two isomers. After separation byHPLC, 1.8 g of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrileand 1.2 g of 4-methyl-6-oxo-1,6-dihydro-2,4′-bipyridine-5-carbonitrilewere obtained. The identity of6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile wasestablished by nOE analysis. ¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (br. s.,1H), 8.75 (d, 2H), 7.58 (d, 2 H), 6.37 (s, 1H), 2.31 (s, 3H).

12c) 3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one

To an ice bath cooled THF (100 mL) solution of6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile (4 g, 18.9mmol) was added NaBH₄ (1.43 g, 37.9 mmol), and I₂ (4.81 g, 18.9 mmol),and the mixture was stirred for 0.5 h. The reaction mixture was thenheated at reflux for 4 h. After cooling to 0° C., the reaction mixturewas adjusted to pH 5 with 4 N HCl. The mixture was concentrated in vacuoto give the crude compound, which was purified by HPLC to give3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one (1.9 g, 31%) as a TFAsalt. LCMS MH+=216.0 ¹H NMR (400 MHz, DMSO-d₆ in D₂O) δ 8.87 (d, 2H),7.87 (d, 2H), 6.13 (s, 1H), 3.65 (br s, 2H), 2.17 (s, 3H).

Intermediate 13 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone

13a) Ethyl cyclobutanecarboxylate

To a solution of cyclobutanecarboxylic acid (50 g, 500 mmol) in EtOH(1.2 L) was slowly added H₂SO₄ (20 mL) at room temperature. The solutionwas stirred at reflux overnight, and then cooled and poured into H₂O.The aqueous layer was extracted with ether. The combined organic layerswere washed with brine, dried over Na₂SOl₄, and concentrated in vacuo togive ethyl cyclobutanecarboxylate as a colorless oil (44 g, 69%).

¹H NMR (400 MHz, CDCl3-d₃) δ 4.04 (q, 2H), 3.04 (m, 1H), 2.12 (m, 4H),1.88 (m, 2H), 1.18 (t, 3H).

13b) 1-cyclobutyl-1,3-butanedione

To a solution of NaNH₂ (11.7 g, 91 mmol) in anhydrous ether (150 mL)under N₂ at 30° C. was added dropwise a mixture of ethylcyclobutanecarboxylate (19.2 g, 150 mmol) and acetone (21.75 g, 375mmol). After addition, the reaction mixture was stirred for 4 h, thenpoured onto ice water with stirring. Ether was added and the unreactedcomponents were extracted into the organic phase. The clear aqueousextract was acidified to pH 5.0 with 2 N HCl, and then to pH 7.5 withNa₂CO₃. The solution was extracted with ether. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated to give the crudeproduct of 1-cyclobutyl-1,3-butanedione (9.7 g, 76%), which was used inthe next step without further purification. ¹H NMR (400 MHz, CDCl3-d₃)δ5.42 (s, 1H), 3.66 (s, 1H), 2.11-2.23 (m, 4H), 2.02 (s, 3H), 1.93-1.99(m, 2H).

13c) 6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile and4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a solution of 1-cyclobutyl-1,3-butanedione (1.5 g, 10.7 mmol) andcyanoacetamide (1.07 g, 12.8 mmol) in EtOH (25 mL) was added piperidine(1.08 g, 12.8 mmol) at 75° C. After addition, the mixture was stirredwith warming to reflux. After 1 h, the mixture was cooled to roomtemperature during which time precipitation occurred. The contents werefiltered, and the filtered solid suspended in water and stirred for 1 h.The heterogenous mixture was filtered and dried to give a mixture of6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile and4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.14 g,57%). ¹H NMR (400 MHz, DMSO-d₆ in D20) δ 12.15-12.30 (br s, 2H), 6.39(s, 1H), 6.34 (s, 1H), 2.40-2.28 (m, 7 H), 2.23-2.25 (m, 3H), 2.18-2.21(m, 4H), 1.99-2.11 (m, 2H), 1.84-1.90 (m, 2H).

13d) 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone and3-(aminomethyl)-4-cyclobutyl-6-methyl-2(1H)-pyridinone

To an ice bath cooled THF (100 mL) solution of6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile and4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (6 g, 32mmol) was added NaBH₄ (2.73 g, 71.8 mmol), and 12 (8.3 g, 32 mmol), andthe mixture was stirred for 30 min The reaction mixture was then heatedat reflux for 3 h. After cooling to 0° C., the reaction mixture wasadjusted to pH 5 with 6 N HCl. The contents were dried, filtered, andconcentrated in vacuo. The crude product was purified by HPLC to give amixture of 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone and3-(aminomethyl)-4-cyclobutyl-6-methyl-2(1H)-pyridinone (5.6 g, 91%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.60-11.70 (br s, 2H), 7.85 (br s, 4H),6.15 (s, 1H), 6.03 (s, 1H), 3.72-3.79 (m, 2H), 3.29-3.33 (m, 2H), 2.16(s, 6H), 2.05-2.10 (m, 6H), 1.88-1.93 (m, 4H), 1.69-1.79 (m, 4H).

13e) 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamateand 1,1-dimethylethyl[(4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate

To an ice bath cooled solution of3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone and3-(aminomethyl)-4-cyclobutyl-6-methyl-2(1H)-pyridinone (3.5 g, 18 mmol)in THF (10 mL) and DMF (10 mL) were added Boc₂O (4.68 g, 21.8 mmol) andtriethylamine (5.4 g, 54 mmol). The contents were then stirred for 30min at 30° C. The reaction was quenched by addition of ice water, duringwhich time precipitation occured. The reaction mixture was filtered anddried to give a mixture of the crude products. The crude products wereseparated by HPLC to give 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate(2.1 g, 20%) and 1,1-dimethylethyl[(4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate(1 g, 9.5%). Data for 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate:¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (br s, 1H), 6.49 (br s, 1H), 5.86 (brs, 1H), 3.85 (br s, 2H), 1.97-2.14 (m, 7H), 1.87-1.94 (m, 1H), 1.72-1.77(m, 1H), 1.28 (s, 9H).

13f) 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinonehydrochloride

A solution of 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3pyridinyl)methyl]carbamate(2.1 g, 7.2 mmol) in 4 N HCl (in 15 mL 1,4 dioxane) was heated to 60° C.for 1 h. The mixture was cooled to room temperature. The mixture wasfiltered and dried to give3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone as an HCl salt(1.95 g, 90%). LCMS MH+=193.1 ¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (br s,1H), 8.01 (s, 3H), 6.04 (s, 1H), 3.74 (d, 2H), 3.32-3.39 (m, 1H), 2.22(s, 3H), 2.17-2.20 (m, 2H), 2.06-2.11 (m, 2H), 1.85-1.95 (m, 1H),1.71-1.79 (m, 1H).

Intermediate 143-(aminomethyl)-6-methyl-4-[(methyloxy)methyl]-2(1H)-pyridinone

14a) 1-(methyloxy)-2,4-pentanedione

To a solution of sodium (5.83 g, 243.3 mmol) in dry toluene (62.5 mL)was added ethyl (methyloxy)acetate (24 g, 203.4 mmol) at −5° C. Afterstirring for 3 h, acetone (14 g, 231.4 mmol) was slowly added, uponwhich the mixture became brown and viscous. Next added 72 mL oftert-butyl methyl ether, and the reaction mixture was stirred at roomtemperature for 12 h, after which time the sodium salt precipitated.After collection and washing with additional tert-butyl methyl ether,the sodium salt was dissolved in 46 mL of 20% H₂SO₄. The contents wereextracted with tert-butyl methyl ether and the organic layersconcentrated to afford 1-(methyloxy)-2,4-pentanedione (9.76 g, 36.9%).¹H NMR (400 MHz, CDCl3-d₃) δ 5.76 (s, 1H), 3.96 (s, 2H), 3.38 (s, 3H),2.07 (s, 3H).

14b)6-methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

1-(methyloxy)-2,4-pentanedione (9.51 g, 73.12 mmol) and cyanoacetamide(6.17 g, 73.12 mmol) were dissolved in EtOH (76 mL) and heated untilhomogenous (ca. 75° C.). Piperidine (6.25 g, 73.12 mmol) was added andthe reaction mixture heated at reflux for 20 mins, followed by coolingto room temperature. The contents were filtered to give a solid whichwas suspended in 140 mL water and stirred vigorously for 20 min Theheterogenous mixture was filtered to afford6-methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile(7.8 g, 65.6%). LCMS MH+=179.0 ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (br s,1H), 6.26 (s, 1H), 4.40 (s, 2H), 3.29 (s, 3H), 2.25 (s, 3H).

14c) 3-(aminomethyl)-6-methyl-4-[(methyloxy)methyl]-2(1H)-pyridinone

6-methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile(1.000 g, 5.61 mmol) was suspended in acetic acid (150 ml) and thesolution passed through an H-cube instrument equipped with Raney-Nicartridge at a rate of 1 mL/min at 50 psi and 60° C. After 18 h. theacetic acid was removed under reduced pressure and the remaining residuewas dissolved in MeOH. The methanolic solution was passed through a 0.2μm teflon syringe filter. The methanolic filtrate was purified byreverse phase HPLC (Gemini 50×100 5 μm column. Run 1: 3 min, 90-10%. Run2, 5 min 0-10%. Run 3, 10 min, 0-20%.. The product fractions wereconcentrated to dryness on a Genevac HT-4 instrument to afford3-(aminomethyl)-6-methyl-4-[(methyloxy)methyl]-2(1H)-pyridinone as apale grey waxy solid (900 mg, 70.2% yield) LCMS MH+=183.0 ¹H NMR (400MHz, DMSO-d₆) δ 8.40 (br. s., 1H), 6.10 (s, 1H), 4.39 (s, 2H), 3.66 (br.s., 2H), 3.32 (s, 3H), 2.19 (s, 3H).

Intermediate 153-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone and3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1H)-pyridinone

15a) 1-phenyl-2,4-pentanedione

To a solution of NaNH₂ (19.02 g, 480 mmol) in anhydrous ether (400 mL)under N₂ at −5° C. was added dropwise ethyl phenylacetate (19.2 g, 150mmol) and then acetone (21.23 g, 370 mmol) with vigorous stirring. Afteraddition, the reaction mixture was stirred at room temperatureovernight. The mixture was then acidified to pH 4.0-5.0 with 1 N HCl.The organic layer was separated and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography to give1-phenyl-2,4-pentanedione (18.32 g, 44%). ¹H NMR (400 MHz, CDCl3-d₃) δ15.49 (br s, 1H), 7.33-7.45 (m, 5H), 5.53 (s, 1H), 3.66 (s, 2H), 2.10(s, 3H).

15b) 6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrileand 4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile

1-phenyl-2,4-pentanedione (18.32 g, 104 mmol) and cyanoacetamide (8.74g, 104 mmol) were dissolved in EtOH (104 mL) and heated until homogenous(ca. 75° C.). Piperidine (8.86 g, 104 mmol) was added and the reactionmixture heated at reflux for 15-30 min followed by cooling to roomtemperature, during which time precipitation occurred. The heterogenouscontents were filtered to give a solid which was suspended in 200 mLwater and stirred vigorously for 20 min The heterogenous mixture wasfiltered to afford6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile and4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile(12.06 g, 52%). LCMS MH+=225.1 ¹H NMR (400 MHz, DMSO-d₆) (mixture ofcompounds) δ 7.21-7.31 (m, 10H), 6.06 (s, 2H), 3.89 (s, 2H), 3.79 (s,2H), 2.24 (s, 3H), 2.15 (s, 3H).

15c) 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone and3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1H)-pyridinone

Sodium acetate (6.14 g, 74.8 mmol), Pd/C (0.65 g, 1 mmol), and platinum(II) oxide (45 mg, 1 mmol) were placed in a dried Parr bottle equippedwith nitrogen inlet. A small amount of acetic acid was added to wet thecatalysts. A solution of6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinecarb onitril e and4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinecarbonitrile (6 g,26.7 mmol) in acetic acid (300 mL) was added to the vessel. The contentswere sealed and hydrogenated on Parr shaker at 45 psi for 12 h. Thereaction mixture was filtered and washed with acetic acid. The filtratewas removed under reduced pressure. The residue was washed with methanoland filtered to afford a crude mixture of3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone and3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1H)-pyridinone. The reactionwas run in duplicate to afford a total crude recovery of 14.5 g. To asolution of the above crude product mixture (4.0 g, 17.5 mmol) in THF(10 mL) and DMF (10 mL) was added di-tert-butoxycarbonyl anhydride (5.0g, 23.4 mmoL) and triethylamine (5.2 g, 52.5 mmol) at 0° C. The reactionmixture was stirred with warming to room temperature and then stirredfor an additional 4 h. The contents were diluted with ice water and thenfiltered. The collected solid was dried and the products separated byHPLC to furnish 1.2 g of 1,1-dimethylethyl{[4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}carbamate(¹H NMR (400 MHz, DMSO-d₆) δ 11.55-1.60 (br s, 1H), 7.20-7.29 (m, 5H),5.85 (s, 1H), 3.92 (s, 2H), 3.90 (s, 2H), 2.10 (s, 3H), 1.32 (s, 9H) and1.0 g of 1,1-dimethylethyl{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}carbamate(¹H NMR (400 MHz, DMSO-d₆) δ 11.50-11.55 (br s, 1H), 7.18-7.25 (m, 5H),5.75 (s, 1H), 4.02 (s, 2H), 3.85 (s, 2H), 2.05 (s, 3H), 1.32 (s, 9H).

15d) 3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1H)-pyridinonehydrochloride

A solution of 1,1-dimethylethyl{[4-methyl-2-oxo-6-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}carbamate(1.2 g, 3.66 mmol) in 4N HCl (in 15 mL 1,4 dioxane) was heated to 60° C.for 1 h. The mixture was cooled to room temperature. The mixture wasfiltered and dried to give3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1H)-pyridinone as an HClsalt (0.725 g, 87%). LCMS MH+=229.1 ¹H NMR (400 MHz, DMSO-d₆) δ11.9-12.0 (br s, 1H), 7.99 (br s, 3H), 7.20 (s, 5H), 5.97 (s, 1H),3.72-3.75 (m, 4H), 2.17 (s, 3H).

15e) 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinonehydrochloride

A solution of 1,1-dimethylethyl{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}carbamate(1.0 g, 3.0 mmol) in 4N HCl (in 15 mL 1,4 dioxane) was heated to 60° C.for 1 h. The mixture was cooled to room temperature. The mixture wasfiltered and dried to give3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone as an HClsalt (0.600 g, 86%). LCMS MH+=229.1 ¹H NMR (400 MHz, DMSO-d₆) δ11.9-12.0 (br s, 1H), 8.03 (br s, 3H), 7.16-7.30 (m, 5H), 5.84 (s, 1H),3.91 (s, 2H), 3.81 (s, 2H), 2.10 (s, 3H).

Intermediate 163-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone

a) 5-(4-morpholinyl)-3-pentyn-2-one

To a cooled (−40° C., CH₃CN/CO₂) solution of 4-(2-propyn-1-yl)morpholine(2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe underN₂ a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00mmol). The reaction was stirred for 1 hr then a solution ofN-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was addedin one portion. The reaction was stirred for 2 hr (allowed to slowlywarm to RT), quenched with aq. NH₄Cl, extracted with EtOAc, washed withbrine, dried (Na₂SO₄), filtered and evaoprated to dryness under vacuum.The remaining was purified by silica gel chromatography (Analogix,SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combinedand evaporated to dryness to give the product5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.62-3.57 (m, 4 H), 3.56 (s, 2H), 2.49-2.43 (m, 4 H), 2.34 (s, 3 H). MS(ES)+ m/e 168.0 [M+H]⁺.

b)6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol).The reaction was stirred for 15 min then a solution of5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was addedto the reaction in one portion. (The reaction quickly turned dark red.)The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried undervacuum overnight. The reamaining dark solid was triturated with asolution of (9:1) CH₂Cl₂, MeOH (50 mL), filtered from insolublematerial, washed with (9:1) CH₂Cl₂, MeOH, and the filtrate evaporated todryness under vacuum. The dark solid was triturated with a solution of(1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes,and dried under vacuum to give a brown solid (removed a lot of fastrunning non-polar impurities). The crude product was purified by silicagel chromatography (Analogix, SF25-60 g, 0 to 15% CH₂Cl₂/20%(5% NH₄OH inMeOH) in CH₂Cl₂). The pure fractions were combined, evaporated todryness, triturated with hexanes and dried under vacuum to give theproduct6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile(0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (br. s., 1 H), 6.34 (s, 1 H),3.63-3.56 (m, 4 H), 3.48 (s, 2 H), 2.45-2.36 (m, 4 H), 2.27 (s, 3 H)MS(ES)+ m/e 234.1 [M+H]⁺.

c) 3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone

A clear solution of6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile(0.60 g, 2.57 mmol) in HOAc (20 mL) was treated on an H-Cube apparatus(50 psi, 60° C., 1 mL/min, Raney Nickel cartridge) for 18 hr overnight.LCMS showed that the reaction was complete. The reaction was evaporatedto dryness, taken up in a small volume of MeOH and treated with 4 N HClin dioxane (5 mL, 20.00 mmol). The mixture was evaporated to drynessunder vacuum (began to ppt. out during evaporation), triturated withEt2O, filtered and dried under vacuum to give the product3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone (0.76g, 2.450 mmol, 95% yield) as a light grey solid. ¹H NMR (400 MHz,DMSO-d₆) δ 6.39 (s, 1 H), 4.28 (s, 2 H), 3.99 (s, 2 H), 3.87 (br. s., 4H), 3.27 (br. s., 4 H), 2.22 (s, 3 H). MS(ES)+ m/e 238.0 [M+H]⁺ (weak),221.3 [M+H]⁺ —NH₃ (strong).

Intermediate 17 tert-Butyl(5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate

a) Ethyl 4-ethoxy-2-oxopent-3-enoate

To a stirred solution of ethyl 2,4-dioxopentanoate (36.5 g, 231 mmol)and triethyl orthoformate (41 mL, 246 mmol) in ethanol (60 mL) was addedammonium chloride (3.7 g, 69 mmol). The suspension was stirred at RTovernight. LCMS showed that the reaction was mostly complete.(Hydrolyzes on LCMS to some degree?) The reaction was concentrated undervacuum. The remaining oil was taken up in Et₂O (300 mL), filtered toremove insolubles, rinsed with Et₂O, and concentrated under vacuum. Theproduct was obtained by short path distillation under vacuum (bp 70 to77° C. at 0.09 mmHg) to give the product ethyl4-ethoxy-2-oxopent-3-enoate (36.5 g, 47.3 mmol, 79% yield) as a lightyellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.24 (s, 1 H), 4.32 (q, J=7.2 Hz, 2 H),4.02 (q, J=6.9 Hz, 2 H), 2.41 (s, 3 H), 1.41 (t, J=7.1 Hz, 3 H), 1.39(t, J=7.2 Hz, 3 H). MS(ES)+ m/e 186.8 [M+H]⁺, 208.8 M+Na⁺.

b) ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate

To a stirred solution of ethyl 4-ethoxy-2-oxopent-3-enoate (22.5 g, 121mmol) and 2-cyanoacetamide (9.0 g, 107 mmol) in acetone (250 mL) wasadded potassium carbonate (15.8 g, 114 mmol). The reaction was refluxed(85° C. oil bath) for 10 hr (the reaction formed a thick ppt. in a deepred solution). The slurry was added to cold 1 N HCl (230 mL) in ice.After stirring for 30 min the suspension was filtered, washed with waterand dried under vacuum to give the product ethyl5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (14.51 g, 70.4mmol, 65.7% yield) as a light pink solid.

¹H NMR (400 MHz, DMSO-d₆) M2.60 (br. s., 1 H), 7.05 (br. s., 1 H), 4.34(q, J=7.1 Hz, 2 H), 2.45 (s, 3 H), 1.32 (t, J=7.1 Hz, 3 H). MS(ES)+ m/e206.8 [M+H]⁺.

c) ethyl 5-cyano-6-methoxy-4-methylpicolinate

To a stirred suspension of ethyl5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (2.0 g, 9.70mmol) in CH₂Cl₂ (25 mL) was added trimethyloxonium tetrafluoroborate(2.0 g, 13.52 mmol). The reaction was rinsed down with CH₂Cl₂ andstirred at RT for 24 h. (The reaction eventually cleared up.) To thereaction was added 1 N NaOH (75 mL). After stirring for 10 minutes themixture was poured into a separatory funnel. The CH₂Cl₂ phase wasremoved, dried (Na2SO₄), filtered and concentrated under vacuum.Purification by silica gel chromatography (Analogix SF25-40 g, 50 to100% CH₂Cl₂ in hexanes) gave the product ethyl5-cyano-6-methoxy-4-methylpicolinate (1.13 g, 5.13 mmol, 52.9% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (s, 1 H), 4.37 (q, J=7.1Hz, 2 H), 4.03 (s, 3 H), 2.55 (s, 3 H), 1.33 (t, J=7.2 Hz, 3 H). MS(ES)+m/e 221.2 [M+H]⁺.

d) 5-cyano-6-methoxy-4-methylpicolinic acid

To a stirred solution of ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.0g, 4.54 mmol) in MeOH (30 mL) and THF (10 mL) was added 6 N NaOH (2 mL,12.00 mmol). The suspension was heated to 60° C. and stirred for 2 h.(The reaction cleared up right away.) LCMS indicated that the reactionwas complete. The reaction was cooled to RT and concentrated to neardryness. The slurry was neutralized with 6 N HCl (2 mL) diluted withwater, filtered, washed with water and dried under vacuum to give theproduct 5-cyano-6-methoxy-4-methylpicolinic acid (0.76 g, 3.95 mmol, 87%yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 3.65 (br. s., 1 H), 7.73 (s, 1 H), 4.03 (s,3 H), 2.54 (s, 3 H). MS(ES)+ m/e 192.9 [M+H]⁺.

e) tert-butyl (5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate

To a stirred solution of 5-cyano-6-methoxy-4-methylpicolinic acid (0.75g, 3.90 mmol) in tert-butanol (25 mL) was added triethylamine (0.7 mL,5.02 mmol). After the reaction became clear DPPA (1 mL, 4.64 mmol) wasadded dropwise over 5 minutes. The reaction was slowly heated to 100° C.and stirred for 4 h. The reaction was cooled to RT and evaporated todryness under vacuum. Purified by silica gel chromatography (Analogix,SF25-60 g, 0 to 20% EtOAc in hexanes) to give, after trituration andfiltration from hexanes, the product tert-butyl(5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.61 g, 2.317 mmol,59.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 7.44 (s, 1 H), 3.91 (s, 3 H), 2.40 (s, 3 H), 1.48 (s, 9 H).MS(ES)+m/e 264.0 [M+H]⁺.

f) tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate

A clear solution of tert-butyl(5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.60 g, 2.279 mmol)in HOAc (5 mL) and ethanol (20 mL) was treated on an H-Cube apparatus(50 psi, 40° C., 1 mL/min, Raney Nickel cartridge) for 18 h. LCMS showedthat the reaction was complete (86% pure). The reaction was evaporatedto dryness under vacuum. Purified by silica gel chromatography(Analogix, SF25-60 g, 0 to 12% (5% NH₄OH/MeOH) in CH₂Cl₂). The purefractions were combined and evaporated to dryness under vacuum to givethe product tert-butyl(5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.42 g, 1.571mmol, 68.9% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33(s, 1 H), 7.16 (s, 1 H), 3.80 (s, 3 H), 3.57 (s, 2 H), 2.28 (s, 3 H),1.46 (s, 9 H). MS(ES)+ m/e 268.1 [M+H]⁺.

Intermediate 18[5-(Aminomethyl)-4-methyl-6-(methyloxy)-2-pyridinyl]methanol

a) 6-(Hydroxymethyl)-2-methoxy-4-methylnicotinonitrile

To a stirred suspension of ethyl 5-cyano-6-methoxy-4-methylpicolinate(5.0 g, 22.70 mmol) and calcium chloride (10 g, 90 mmol) intetrahydrofuran (50 mL) and ethanol (50.0 mL) at 0° C. in an ice bathwas added sodium borohydride (2.5 g, 66.1 mmol). The reaction was slowlyallowed to warm to RT and stirred for 18 h. A large amount of ppt.formed and LCMS showed that the reaction was complete. An equal volumeof EtOAc was added and the reaction stirred for 1 h. The suspension wasfiltered through a pad of Celite and washed with EtOAc. The filtrate wastransferred to a separatory funnel, washed with aq. NH₄Cl, brine, dried(Na₂SO₄), filtered and concentrated under vacuum. Purification by silicagel chromatography (Analogix, SF40-120 g, 0 to 30% EtOAc in CH₂Cl₂) gavethe product 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (3.75 g,21.05 mmol, 93% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.16 (s, 1 H), 5.61 (t, J=5.8 Hz, 1 H), 4.51 (d, J=5.8 Hz, 2 H), 3.94(s, 3 H), 2.47 (s, 3 H). MS(ES)+ m/e 179.1 [M+H]⁺.

b) (5-(Aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol

A clear solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile(0.50 g, 2.81 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on anH-Cube apparatus (50 psi, 40° C., 1 mL/min, Raney Nickel cartridge) for18 hr overnight. LCMS showed that the reaction was complete (crudecontained 57% product and 43% dimeric side product). The reaction wasevaporated to dryness under vacuum. Purified by silica gelchromatography (Analogix, SF25-40 g, 0 to 12% (5% NH₄OH in MeOH) inCH₂Cl₂) (step gradient to 8% to elute off the dimeric side product thento 12% to elute off the product). The pure fractions were combined andevaporated to dryness under vacuum to give the product(5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.30 g, 1.646mmol, 58.7% yield) as a white solid. MS(ES)+ m/e 183.1 [M+H]⁺, 166.1[M+H]⁺—NH₃.

Intermediate 19 tert-Butyl45-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate

a)6-((1,3-Dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile

To a stirred solution of6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (1.50 g, 8.42 mmol),phthalimide (1.3 g, 8.84 mmol) and triphenylphosphine (2.3 g, 8.77 mmol)in tetrahydrofuran (THF) (50 mL) at 0° C. in an ice bath was addeddropwise DIAD (1.8 mL, 9.26 mmol). Within minutes a white suspensionformed. Additional THF (˜50 mL) was added to allow stirring. Thereaction was allowed to warm to RT and stirred for 3 h. LCMS showed thatthe reaction was complete. The reaction was evaporated to dryness undervacuum. The remaining solid was triturated with a small volume of EtOAc,filtered, washed with a small volume of EtOAc, then dried under vacuumto give the product6-((1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile(2.12 g, 6.90 mmol, 82% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.00-7.92 (m, 2 H), 7.92-7.87 (m, 2 H), 7.15 (s, 1 H), 4.86(s, 2 H), 3.74 (s, 3 H), 2.43 (s, 3 H). MS(ES)+ m/e 308.2 [M+H]⁺.

b) tert-Butyl ((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate

To a stirred fine suspension of6-((1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile(2.1 g, 6.83 mmol) in Ethanol (100 mL) was added hydrazine monohydrate(1.4 ml, 28.9 mmol). The reaction was stirred at RT for 18 h. LCMSshowed that the reaction was done. The thick white suspension wasfiltered, pressed dry, washed with EtOH, and the filtrate evaporated todryness under vacuum. The remaining solid was taken up inDichloromethane (50 ml), filtered to remove additional insolublematerial, and washed with CH₂Cl₂. To the clear filtrate with stirringwas added Boc₂O (1.809 ml, 7.79 mmol). After stirring at RT for 1 hrLCMS showed that the reaction was complete. The reaction wasconcentrated under vacuum and purified by silica gel chromatography(Analogix, SF25-60, 0 to 10% EtOAc in hexanes). The pure fractions werecombined and evaporated to dryness to give the product tert-butyl((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (1.42 g, 5.12mmol, 74.9% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (t, J=6.1 Hz, 1 H), 6.91 (s, 1 H), 4.16(d, J=6.1 Hz, 2 H), 3.96 (s, 3 H), 2.45 (s, 3 H), 1.41 (s, 9 H). MS(ES)+m/e 278.2 [M+H]⁺.

c) tert-Butyl((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate

A clear solution of tert-butyl((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.65 g, 2.344mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cubeapparatus (50 psi, 40° C., 1 mL/min, Raney Nickel cartridge) for 18 hrovernight. LCMS showed that the reaction was complete. The reaction wasevaporated to dryness under vacuum. Purified by silica gelchromatography (Analogix, SF25-60 g, 0 to 10% (5% NH₄OH/MeOH) inCH₂Cl₂). The pure fractions were combined and evaporated to drynessunder vacuum to give the product tert-butyl((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.58g, 2.061 mmol, 88% yield) as a clear thick oil. ¹H NMR (400 MHz,DMSO-d₆) δ 7.31 (t, J=6.1 Hz, 1 H), 6.63 (s, 1 H), 4.06 (d, J=6.3 Hz, 2H), 3.84 (s, 3 H), 3.61 (s, 2 H), 2.29 (s, 3 H), 1.53 (br. s., 2 H),1.41 (s, 9 H). MS(ES)+ m/e 282.2 [M+H]⁺.

Intermediate 20

The title compound was prepared in the same manner as described for3-(aminomethyl)-4-ethyl-6-methyl-2(1H)-pyridinone (Intermediate 10c).LCMS (ES+) m/z=195.22 (M+H). ¹H NMR (DMSO-d₆, 400 MHz): δ 0.809-0.774(t, 3H, J=6.8 Hz), 1.113-1.097 (d, 3H, J=6.4 Hz), 1.504-1.468 (t, 2H,J=7.2 Hz), 2.184 (s, 3H), 2.839-2.822(d, 1H, J=6.8 Hz), 3.822 (s, 2H),6.059 (s, 1H), 8.315 (bs, 2H).

Intermediate 21 2-Methoxy-5-(tributylstannyl)thiazole

To a stirred solution of 2-methoxythiazole (5 g, 43.4 mmol) intetrahydrofuran (THF) (50 mL) was added n-BuLi (35.3 mL, 56.4 mmol) andthe contents stirred at −78° C. After 15 min, tributylchlorostannane(14.13 mL, 52.1 mmol) was added and the mixture stirred with warming toroom temperature over a 3 h period. The reaction mixture was quenchedwith water (20 mL) and the contents extracted with ether (25 mL). Theorganic layer was separated and dried over anhydrous sodium sulphate,filtered, and the filtrate concentrated in vacuo to afford the crudeproduct (6 g). The crude product was purified by silica gel columnchromatography (eluent: 2% EtOAc/Hexane) to afford2-methoxy-5-(tributylstannyl)thiazole (4 g, 22%) as yellow liquid. ¹HNMR (400 MHz, CDCl3-d₃) δ ppm 0.90-0.98 (m, 9H), 1.05-1.15 (m,6H),1.30-1.40 (m, 6H), 1.50-1.65 (m, 6H), 4.04 (s, 3H), 7.03 (s, 1H).LCMS(ES) [M+H]⁺ 405.99.

Intermediate 22 2-Methoxythiazol-5-yl)boronic acid

To a stirred solution of 5-bromo-2-methoxythiazole (500 mg, 2.58 mmol)in tetrahydrofuran (THF) (15 mL) was added triisopropyl borate (0.598mL, 2.58 mmol) and then n-BuLi (2.416 mL, 3.87 mmol), and the contentsstirred at −78° C. for 3 h. The reaction mixture was quenched withaq.NH₄Cl (5 mL) and the contents extracted with ethyl acetate (15 mL).The organic layer was separated and dried over anhydrous sodiumsulphate, filtered, and the filtrate concentrated in vacuo to afford thetitle compound (400 mg), which was used without further purification.

Intermediate 23 Methyl 2-methyl-3-((tetrahydrofuran-3-yl)oxy)benzoate

To a solution of methyl 3-hydroxy-2-methylbenzoate (150 mg, 0.9 mmol) in5 mL of THF were added tetrahydrofuran-3-ol (159 mg, 1.8 mmol),triphenylphosphine (474 mg, 1.8 mmol) and DIAD (0.49 ml, 2.5 mmol) andthe mixture was stirred at room temperature overnight. The mixture wasthen evaporated and the residue preabsorbed on silica gel and purifiedusing normal phase chromatography: Heptane/EtOAc (12 g column, gradient0 to 100%) to give a colorless oil (145 mg, 67% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.93-2.01 (m, 1 H) 2.17-2.26 (m, 1 H) 2.28-2.32 (m, 3 H)3.75-3.81 (m, 2 H) 3.82 (s, 3 H) 3.83-3.88 (m, 1 H) 3.91 (dd, J=10.11,4.55 Hz, 1 H) 5.03-5.10 (m, 1 H) 7.13-7.19 (m, 1 H) 7.26 (t, J=7.83 Hz,1 H) 7.29-7.34 (m, 1 H). MS(ES) [M+H]⁺237.1.

Intermediate 24 Methyl 2-methyl-3-((1-methylpyrrolidin-3-yl)oxy)benzoate

Following the procedure described for Intermediate 23, the titlecompound was prepared as a brownish oil (236 mg, 90% yield). MS(ES)[M+H]⁺ 250.1.

Intermediate 25 Ethyl 2-methyl-3-(tetrahydro-2H-pyran-4-yloxy)benzoate

Following the procedure described for Intermediate 23, the titlecompound was prepared as a brownish oil (100 mg, 43% yield). MS(ES)[M+H]⁺ 251.1.

EXAMPLES Example 15-Bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide

a) Methyl 5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoate

To a 100 mL round bottom was added methyl3-amino-5-bromo-2-methylbenzoate (1 g, 4.10 mmol) and acetone (3.01 mL,41.0 mmol), followed by methanol (50 mL). Zinc chloride (1.675 g, 12.29mmol) was added followed by sodium cyanoborohydride (1.030 g, 16.39mmol). The reaction stirred at 40° C. for 20 h. The reaction was pouredonto ice water (50 mL) that was saturated with NH₄Cl and was stirred for20 min then rested for 10 min and filtered. The solid was rinsed withwater (2×20 mL) to give the above product as an off-white solid. (500mg, 1.573 mmol, 38.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.96 (d,J=2.02 Hz, 1 H) 6.82 (d, J=1.77 Hz, 1 H) 4.93 (d, J=8.08 Hz, 1 H) 3.79(s, 3 H) 3.59-3.70 (m, 1 H) 2.10 (s, 3 H) 1.17 (d, 6 H). MS(ES) [M+H]⁺288.1.

b) 5-Bromo-2-methyl-3-[(1-methylethyl)amino]benzoic acid

To a 10 ml vial was added methyl5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoate (500 mg, 1.747 mmol),methanol (2 mL) and tetrahydrofuran (THF) (10 mL). 6 M NaOH (0.874 mL,5.24 mmol) was added and the reaction stirred at 40° C. for 20 h. Thereaction was cooled and evaporated. The residual water was poured ontodilute acidic ice water (6 N HCl) (5 mL) pH ˜4. The slurry was stirred20 min (rested 10 min) then filtered. The solid was washed with waterand dried to give the above product (270 mg, 0.962 mmol, 55.1% yield) asan off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.98 (br. s., 1 H)6.95 (s, 1 H) 6.78 (bs, 1 H) 4.87 (bs, 1 H) 3.55-3.72 (m, 1 H) 2.16 (s,3 H) 1.18 (d, J=6.32 Hz, 6 H). MS(ES) [M+H]⁺ 274.2.

c)5-Bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide

To a 50 ml round bottom was added5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoic acid (270 mg, 0.992mmol), 1-hydroxy-7-azabenzotriazole (203 mg, 1.488 mmol) and EDC (285mg, 1.488 mmol) followed by dimethyl sulfoxide (DMSO) (20 mL).N-methylmorpholine (0.327 mL, 2.98 mmol) was added to the reactionfollowed by 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (232 mg,1.290 mmol). The reaction stirred at rt for 72 h. The reaction waspoured onto ice water (10 mL) and was stirred for 20 min (rested for 10min) and filtered. The solid was rinsed with water (10 mL) followed byMeOH/ice water (10 mL/10 mL) to provide the title compound as a tansolid. (299 mg, 0.661 mmol, 66.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 11.48 (br. s., 1 H) 8.08 (t, J=4.67 Hz, 1 H) 6.66 (s, 1 H) 6.52 (d,J=1.52 Hz, 1 H) 5.88 (s, 1 H) 4.74 (d, J=7.83 Hz, 1 H) 4.24 (d, J=4.80Hz, 2 H) 3.54-3.67 (m, 1 H) 2.45-2.48 (m, 2H) 2.12 (s, 3 H) 1.96 (s, 3H) 1.47-1.56 (m, 2 H) 1.16 (d, J=6.32 Hz, 6 H) 0.90-0.94 (m, 3 H).MS(ES) [M+H]⁺ 434.0.

Example 22-Methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-5-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]benzamide

To a 10 ml microwave vial was added5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide(130 mg, 0.299 mmol),1-methyl-445-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyllpiperazine(127 mg, 0.389 mmol) then PdCl2(dppf)-CH₂Cl₂ adduct (24.44 mg, 0.030mmol) followed by 1,4-dioxane (10 mL). To the solution was added sodiumbicarbonate (75 mg, 0.898 mmol) and water (2 mL). The vial was cappedand the reaction stirred on a hot plate at 110° C. for 2 h. The reactionwas cooled and evaporated. The residue was filtered through an acrodiscand purified by reverse phase Gilson HPLC (10-70%acetonitrile/water+0.1% TFA, YMC ODS-A C₁₈ Column 75×30 mm ID S-5 um, 12nM Column 7 minutes). The title compound was isolated as an off whitesolid after extraction of the desired fractions with EtOAc/NaHCO₃ (sataq), evaporation precipitation (from MeOH/water (1/9)) and filtering. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.47 (br. s., 1 H) 8.36 (d, J=2.53 Hz, 1H) 8.00 (t, J=4.93 Hz, 1 H) 7.77 (dd, J=8.84, 2.53 Hz, 1 H) 6.88 (d,J=9.09 Hz, 1 H) 6.74 (d, J=1.01 Hz, 1 H) 6.65 (d, J=1.52 Hz, 1 H) 5.89(s, 1 H) 4.47 (d, J=8.08 Hz, 1 H) 4.28 (d, J=4.80 Hz, 2 H) 3.70-3.81 (m,1 H) 3.48-3.54 (m, 4 H) 2.48-2.49 (m, 2H) 2.39-2.43 (m, 4 H) 2.22 (s, 3H) 2.12 (s, 3 H) 2.04 (s, 3 H) 1.49-1.60 (m, 2 H) 1.20 (d, J=6.32 Hz, 6H) 0.93 (t, 3 H). MS(ES) [M+H]⁺ 531.1.

Example 35-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide

Following the general procedure similar of Example 1c, substituting3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (407 mg, 2.68 mmol) for3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone the title compoundwas prepared (688 mg, 1.642 mmol, 80% yield) as a pale orange solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.47 (br. s., 1 H) 8.05-8.20 (m, 1 H) 6.66(s, 1 H) 6.53 (s, 1 H) 5.86 (s, 1 H) 4.73 (d, J=8.08 Hz, 1 H) 4.23 (d,J=4.80 Hz, 2 H) 3.63-3.58 (m, 1 H) 2.18 (s, 3 H) 2.11 (s, 3 H) 1.95 (s,3 H) 1.16 (d, J=6.3 Hz 6 H). MS(ES) [M+H]⁺ 408.0.

Example 45-Bromo-2-methyl-3-[(1-methylethyl)amino]-N-{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}benzamide

Following the general procedure of Example 1c, substituting3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (101 mg,0.441 mmol) for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone, theabove compound was prepared (38 mg, 0.077 mmol, 21.01% yield) as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.55 (br. s., 1 H) 8.18-8.25 (m,1 H) 7.27-7.35 (m, 2 H) 7.18-7.26 (m, 3 H) 6.66 (d, J=1.77 Hz, 1 H) 6.49(d, J=1.77 Hz, 1 H) 5.76 (s, 1 H) 4.74 (d, J=8.08 Hz, 1 H) 4.31 (d,J=5.05 Hz, 2 H) 3.92 (s, 2 H) 3.62 (s, 1 H) 2.08 (s, 3 H) 1.94 (s, 3 H)1.16 (d, J=6.32 Hz, 6 H). MS(ES) [M+H]⁺ 481.9

Example 52-Methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-5-[6-(methyloxy)-3-pyridinyl]benzamide

Following the general procedure of Example 2, substituting2-methoxy-5-pyridineboronic acid (46.5 mg, 0.304 mmol) for1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine,2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-5-[6-(methyloxy)-3-pyridinyl]benzamide(60 mg, 0.127 mmol, 46.0% yield) was isolated as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.48 (br. s., 1 H) 8.40 (d, J=2.27 Hz,1 H) 8.02 (t, J=4.67 Hz, 1 H) 7.94 (dd, J=8.59, 2.27 Hz, 1 H) 6.88 (d,J=8.59 Hz, 1 H) 6.77 (s, 1 H) 6.68 (s, 1 H) 5.89 (s, 1 H) 4.52 (d,J=8.08 Hz, 1 H) 4.29 (d, J=4.80 Hz, 2 H) 3.88 (s, 3 H) 3.78 (d, J=6.57Hz, 1 H) 2.48-2.49 (m, 2H) 2.12 (s, 3 H) 2.05 (s, 3 H) 1.49-1.62 (m, 2H) 1.20 (d, J=6.06 Hz, 6 H) 0.93 (t, 3 H). MS(ES) [M+H]⁺ 463.3.

Example 6N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(methyloxy)-3-pyridinyl]benzamide

Following the general procedure of Example 2, substituting5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide(150 mg, 0.369 mmol) for5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamideand 2-methoxy-5-pyridineboronic acid (46.5 mg, 0.304 mmol) for1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyllpiperazine,N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(methyloxy)-3-pyridinyl]benzamide(110 mg, 0.248 mmol, 67.2% yield) was isolated as an off white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.47 (s, 1 H) 8.41 (d, J=2.02 Hz, 1 H)8.06 (t, J=5.05 Hz, 1 H) 7.94 (dd, J=8.59, 2.53 Hz, 1 H) 6.88 (d, J=8.59Hz, 1 H) 6.77 (s, 1 H) 6.69 (d, J=1.52 Hz, 1 H) 5.86 (s, 1 H) 4.52 (d,J=8.08 Hz, 1 H) 4.27 (d, J=5.05 Hz, 2 H) 3.88 (s, 3 H) 3.71-3.84 (m, 1H) 2.20 (s, 3 H) 2.11 (s, 3 H) 2.05 (s, 3 H) 1.20 (d, J=6.63 Hz, 6 H).MS(ES) [M+H]⁺ 435.1.

Example 74′-[(Dimethylamino)methyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-methyl-5-[(1-methylethyl)amino]-3-biphenylcarboxamide

Following the general procedure of Example 2, substituting5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide(150 mg, 0.369 mmol) for5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamideandN,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine(106 mg, 0.406 mmol) for1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine,4′-[(dimethylamino)methyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-methyl-5-[(1-methylethyl)amino]-3-biphenylcarboxamide(55 mg, 0.112 mmol, 30.4% yield) was isolated as an off white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.46 (br. s., 1 H) 8.06 (t, J=4.93 Hz, 1H) 7.55 (d, J=8.08 Hz, 2 H) 7.33 (d, J=8.08 Hz, 2 H) 6.79 (s, 1 H) 6.71(d, J=1.52 Hz, 1 H) 5.86 (s, 1 H) 4.49 (d, J=8.34 Hz, 1 H) 4.28 (d,J=4.80 Hz, 2 H) 3.71-3.82 (m, 1 H) 3.40 (s, 2 H) 2.20 (s, 3 H) 2.16 (s,6 H) 2.11 (s, 3 H) 2.05 (s, 3 H) 1.21 (d, J=6.32 Hz, 6 H). MS(ES) [M+H]⁺461.1.

Example 85-(6-Amino-3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide

Following the general procedure of Example 2, substituting5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide(150 mg, 0.369 mmol) for5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamideand 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (89mg, 0.406 mmol) for1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazinethe title compound5-(6-amino-3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide(42 mg, 0.094 mmol, 25.5% yield) was isolated as an off white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.47 (s, 1 H) 8.16 (d, J=2.02 Hz, 1 H)8.02 (t, J=5.05 Hz, 1 H) 7.62 (dd, J=8.46, 2.65 Hz, 1 H) 6.69 (d, J=1.26Hz, 1 H) 6.61 (d, J=1.52 Hz, 1 H) 6.49 (d, J=8.59 Hz, 1 H) 5.99 (s, 2 H)5.86 (s, 1 H) 4.43 (d, J=8.34 Hz, 1 H) 4.27 (d, J=5.05 Hz, 2 H)3.70-3.79 (m, 1 H) 2.20 (s, 3 H) 2.11 (s, 3 H) 2.02 (s, 3 H) 1.19 (d,J=6.32 Hz, 6 H). MS(ES) [M+H]⁺ 420.0.

Example 9N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(1-piperazinyl)-3-pyridinyl]benzamide

Following the general procedure of Example 2, substituting5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]benzamide(150 mg, 0.369 mmol) for5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamideand 6-(1-piperazinyl)pyridine-3-boronic acid pinacol ester (117 mg,0.406 mmol) for1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine(127 mg, 0.389 mmol) the title compound was isolated as an off-whitesolidN-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)amino]-5-[6-(1-piperazinyl)-3-pyridinyl]benzamide(50 mg, 0.097 mmol, 26.3% yield) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.47(br. s., 1 H) 8.36 (d, J=2.27 Hz, 1 H) 8.03 (t, J=4.93 Hz, 1 H)7.73-7.81 (m, 1 H) 6.84 (d, J=8.84 Hz, 1 H) 6.74 (d, J=1.52 Hz, 1 H)6.65 (d, J=1.77 Hz, 1 H) 5.86 (s, 1 H) 4.46 (d, J=8.08 Hz, 1 H) 4.27 (d,J=4.80 Hz, 2 H) 3.70-3.83 (m, 1 H) 3.40-3.55 (m, 4 H) 2.75-2.83 (m, 4 H)2.20 (s, 3 H) 2.11 (s, 3 H) 2.03 (s, 3 H) 1.20 (d, J=6.06 Hz, 6 H).MS(ES) [M+H]⁺ 489.1.

Example 10N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide

A stirred solution of5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methylbenzamide(400 mg, 0.984 mmol), (2-methoxythiazol-5-yl)boronic acid (156 mg, 0.984mmol) and cesium carbonate (802 mg, 2.461 mmol) in toluene (10 mL) andwater (1 mL) were degassed with argon for 30 min. Next added Pd(Ph₃P)₄(11.38 mg, 9.84 μmol) and the contents were heated to 110° C. for 16 hin a sealed tube. The contents were concentrated in vacuo and thenextracted with ethyl acetate (50 mL) and washed with water (15 mL). Theorganic layer was separated, dried over anhydrous sodium sulphate,filtered, and concentrated to afford 500 mg of crude product. The crudeproduct was purified by silica gel chromatography (eluent: 3% MeOH/DCM)to afford 130 mg of solid. The contents were again washed with ether (15mL), filtered and dried to afford the title compound (100 mg, 22% yield)as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, 6H,J=6.4 Hz), 2.00 (s, 3H), 2.10 (s, 3H), 2.19 (s, 3H), 3.69-3.74 (m, 1H),4.03 (s, 3H), 4.26 (d, 2H, J=4.9 Hz), 4.54 (d, 1H, J=7.9 Hz), 5.85 (s,1H), 6.56 (d, 1H, J=1.8 Hz), 6.66 (s, 1H), 7.52 (s, 1H), 8.04 (t, 1H,J=4.9 Hz), 11.5 (s, 1H). LCMS(ES) [M+H]⁺ 441.3.

Example 115-Bromo-3-(sec-butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

a) Methyl 5-bromo-3-(sec-butylamino)-2-methylbenzoate

To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5.0 g,20.48 mmol) and butan-2-one (14.77 g, 205 mmol) in methanol (250 mL) wasadded zinc chloride (8.38 g, 61.5 mmol) followed by sodiumcyanoborohydride (5.15 g, 82 mmol) at room temperature. The reactionmixture was stirred at 50° C. for 20 h, and then concentrated underreduced pressure. The contents were washed with water (50 mL) andextracted with EtOAC (150 mL). The organic layer was separated and driedover anhydrous sodium sulphate, filrered, and concentrated to afford thecrude product (5 g). The crude product was purified by silica gelchromatography (eluent: 5% EtOAC/Hexane) to afford the title compound(3.0 g, 48%) as brown coloured liquid. LCMS(ES) [M+H]⁺ 300.0.

b) 5-Bromo-3-(sec-butylamino)-2-methylbenzoic acid

To a suspension of methyl 5-bromo-3-(sec-butylamino)-2-methylbenzoate(3.0 g, 9.99 mmol) in tetrahydrofuran (25 mL) and water (25.00 mL) wasadded LiOH (1.436 g, 60.0 mmol) and the reaction mixture stirred at 70°C. for 16 h. The volatiles were removed in vacuo and the pH adjusted to1-2 using 6 N HCl (15 mL) wherein precipitation ensued. The contentswere filtered and dried to afford the title compound (2.5 g, 87%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (t, 3H, J=7.4 Hz),1.17 (d, 3H, J=6.4 Hz), 1.41-1.54 (m, 1H), 1.57-1.64 (m, 1H), 2.17 (s,3H), 3.37-3.43 (m, 1H), 5.78 (m, 1H), 6.77 (s, 1H), 6.95 (s, 1H),12.8-13.0 (br s, 1H).

c)5-Bromo-3-(sec-butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

To a stirred solution of 5-bromo-3-(sec-butylamino)-2-methylbenzoic acid(1.0 g, 3.49 mmol), EDC (1.005 g, 5.24 mmol), and HOBT (0.803 g, 5.24mmol) in dimethyl sulfoxide (DMSO) (40 mL) was added N-methylmorpholine(1.537 mL, 13.98 mmol) followed by3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, hydrochloride (0.791 g,4.19 mmol). The reaction mixture was stirred at 25° C. for 16 h. Thereaction mixture was poured onto ice water (50 mL), stirred for 10 min,allowed to stand for 10 min, and filtered. The collected solid wasrinsed with water (50 mL) followed by 10% MeOH/ice water (50 mL), andthen diethyl ether (25 mL). The contents were filtered and dried toafford the title compound (750 mg, 51%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.86 (t, 3H, J=7.5 Hz), 1.10 (d, 3H, J=6.4 Hz),1.41-1.48 (m, 1H), 1.55-1.62 (m, 1H), 1.95 (s, 3H), 2.11 (s, 3H), 2.17(s, 3H), 3.34-3.39 (m, 1H), 4.23 (d, 2H, J=4.9 Hz), 4.65 (d, 1H, J=7.9Hz), 5.85 (s, 1H), 6.55 (s, 1H), 6.63 (s, 1H), 8.03 (t, 1H, J=4.9 Hz),11.5 (s, 1H). LCMS(ES) [M+H]⁺ 420.4.

Example 123-(sec-Butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide

A stirred solution of5-bromo-3-(sec-butylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(500 mg, 1.190 mmol) and 2-methoxy-5-(tributylstannyl)thiazole (481 mg,1.190 mmol) in toluene (15 mL) was degassed with argon for 20 min andthen Pd(Ph₃P)₄ (13.75 mg, 0.012 mmol) was added. The reaction mixturewas heated to 120° C. for 16 h in a sealed tube. The contents wereconcentrated in vacuo and the crude product was purified by silica gelchromatography (eluent: 4% MeOH/DCM) to afford the title compound (103mg, 19% yield) as a pale yellow coloured solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.89 (t, 3H, J=7.4 Hz), 1.14 (d, 3H, J=6.4 Hz), 1.44-1.51(m, 1H), 1.57-1.64 (m, 1H), 2.00 (s, 3H), 2.11 (s, 3H), 2.19 (s, 3H),3.45-3.52 (m, 1H), 4.03 (s, 3H), 4.25 (d, 2H, J=4.9 Hz), 4.50 (d, 1H,J=8.4 Hz), 5.85 (s, 1H), 6.55 (d, 1H, J=1.5 Hz), 6.63 (s, 1H), 7.51 (s,1H), 8.03 (t, 1H, J=4.9 Hz), 11.5 (s, 1H). LCMS(ES) [M+H]⁺ 455.3

Example 135-Bromo-2-methyl-3-[methyl(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide

a) Methyl 5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoate

To a 10 ml microwave vial was added methyl5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoate (500 mg, 1.747 mmol),cesium carbonate (1708 mg, 5.24 mmol) and potassium iodide (290 mg,1.747 mmol), followed by acetonitrile (6 mL). Methyl iodide (0.219 mL,3.49 mmol) was added to the solution and the vial was capped and stirredat 60° C. for 4 days. The reaction was poured onto ice water (50 mL)that was saturated with NH₄Cl and was stirred for 20 min The aqueousmixture was extracted with EtOAc. The organic layer was evaporated andpurified by silica gel chromatography (Analogix IF280, 10-30%EtOAc/hexanes, SF25-40 g, 20 minutes) Purification provided methyl5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoate (386 mg, 1.157mmol, 66.2% yield) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.51 (d, J=2.02 Hz, 1 H) 7.35 (d, J=2.02 Hz, 1 H) 3.11-3.23 (m, 1 H)2.56 (s, 3 H) 2.31 (s, 3 H) 1.03 (d, J=6.57 Hz, 6 H) MS(ES) [M+H]⁺300.2.

b) 5-Bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoic acid

Following the general procedure of Example 1b, but substituting methyl5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoate (386 mg, 1.286mmol) for methyl 5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoate, thetitle compound 5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoicacid (213 mg, 0.595 mmol, 46.3% yield) was isolated as a clear oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.39 (d, J=2.27 Hz, 1 H) 7.23 (d, J=2.27Hz, 1 H) 3.18-3.12 (m, 1 H) 2.54 (s, 3 H) 2.29 (s, 3 H) 1.02 (d, J=6.51Hz, 6 H). MS(ES) [M+H]⁺ 288.1.

c)5-Bromo-2-methyl-3-[methyl(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide

Following the general procedure of Example 1c, but substituting5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]benzoic acid (210 mg,0.734 mmol), for 5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoic acid(270 mg, 0.992 mmol), the title compound,5-bromo-2-methyl-3-[methyl(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide(105 mg, 0.229 mmol, 31.3% yield), was prepared as a solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.49 (br. s., 1 H) 8.19 (t, J=4.80 Hz, 1 H) 7.15(d, J=2.02 Hz, 1 H) 7.00 (d, J=2.02 Hz, 1 H) 5.89 (s, 1 H) 4.25 (d,J=5.05 Hz, 2 H) 3.17 (t, J=6.57 Hz, 1 H) 2.53 (s, 3 H) 2.47-2.50 (m, 2H) 2.12 (d, J=2.53 Hz, 6 H) 1.48-1.59 (m, 2 H) 1.02 (d, J=6.57 Hz, 6 H)0.93 (t, J=7.33 Hz, 3 H) MS(ES) [M+H]⁺ 447.8.

Example 145-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropyl(methyl)amino)-2-methylbenzamide

To a stirred solution of5-bromo-3-(isopropyl(methyl)amino)-2-methylbenzoic acid (500 mg, 1.747mmol), EDC (502 mg, 2.62 mmol), and HOBT (401 mg, 2.62 mmol) in dimethylsulfoxide (DMSO) (20 mL) was added N-methylmorpholine (0.768 mL, 6.99mmol), followed by 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride (396 mg, 2.097 mmol). The reaction mixture was stirred at25° C. for 16 h. The reaction mixture was poured onto ice water (25 mL),stirred for 10 min, allowed to stand for 10 min, and then filtered. Thecollected solid was rinsed with water (25 mL), followed by 10% MeOH/icewater (15 mL) and diethyl ether (25 mL). The contents were filtered anddried to afford the title compound (200 mg, 27%) as pale organge solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (d, 6H, J=6.4 Hz), 2.11 (s, 6H),2.18 (s, 3H), 2.53 (s, 3H), 3.14-3.20 (m, 1H), 4.23 (d, 2H, J=4.9 Hz),5.85 (s, 1H), 7.00 (s, 1H), 7.14 (s, 1H), 8.17 (t, 1H, J=4.9 Hz), 11.5(s, 1H). LCMS(ES) [M+H]⁺ 420.5.

Example 15N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropyl(methyl)amino)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide

A stirred solution of5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropyl(methyl)amino)-2-methylbenzamide(500 mg, 1.190 mmol) and 2-methoxy-5-(tributylstannyl)thiazole (481 mg,1.190 mmol) in toluene (15 mL) was degassed with argon for 20 min andPd(Ph₃P)₄ (13.75 mg, 0.012 mmol) was added. The reaction mixture washeated to 120° C. for 16 h in a sealed tube. The contents wereconcentrated in vacuo and the crude residue purified by silica gelchromatography (eluent: 3% MeOH/DCM) to afford 135 mg of solid. Thesolid was triturated with ether (15 mL), filtered, and dried in vacuo toafford the title compound (111 mg, 20%) as pale yellow coloured solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, 6H, J=6.6 Hz), 2.11 (s, 3H),2.16 (s, 3H), 2.20 (s, 3H), 2.58 (s, 3H), 3.16-3.28 (m, 1H), 4.04 (s,3H), 4.26 (d, 2H, J=4.9 Hz), 5.86 (s, 1H), 7.00 (s, 1H), 7.13 (s, 1H),7.59 (s, 1H), 8.14 (s, 1H), 11.5 (s, 1H). LCMS(ES) [M+H]⁺ 455.3.

Example 165-Bromo-3-(sec-butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

a) Methyl 5-bromo-3-(sec-butyl(methyl)amino)-2-methylbenzoate

To a stirred solution of methyl5-bromo-3-(sec-butylamino)-2-methylbenzoate (2.5 g, 8.33 mmol) andformaldehyde (12.40 mL, 167 mmol) in methanol (250 mL) was added zincchloride (3.40 g, 24.98 mmol) followed by sodium cyanoborohydride (2.093g, 33.3 mmol) at room temperature. The mixture was stirred at 50° C. for20 h and then concentrated under reduced pressure. The contents werewashed with water (50 mL) and extracted with EtOAC (150 mL). The organiclayer was separated and dried over anhydrous sodium sulphate, filtered,and concentrated under reduced pressure to afford the crude product (4g). The crude product was purified by silica gel chromatography (eluent:5% EtOAC/Hexane) to afford the title compound (2.0 g, 76%) as colourlessliquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (t, 3H, J=7.4 Hz), 0.95 (d,3H, J=6.4 Hz), 1.38-1.58 (m, 2H), 2.35 (s, 3H), 2.58 (s, 3H), 2.90-2.98(m, 1H), 3.80 (s, 3H), 7.30 (s, 1H), 7.50 (s, 1H). LCMS(ES) [M+H]⁺314.3.

b) 5-Bromo-3-(sec-butyl(methyl)amino)-2-methylbenzoic acid

To a suspension of methyl5-bromo-3-(sec-butyl(methyl)amino)-2-methylbenzoate (2.0 g, 6.37 mmol)in tetrahydrofuran (25 mL) and water (25.00 mL) was added LiOH (0.915 g,38.2 mmol) and the contents stirred at 70° C. for 20 h. The volatileswere removed in vacuo and the pH adjusted to 1-2 using 6 N HCl (15 mL),wherein precipitation ensued. The contents were filtered and dried toafford the title compound (1.5 g, 78%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.84 (t, 3H, J=7.4 Hz), 0.95 (d, 3H, J=6.4 Hz),1.38-1.58 (m, 2H), 2.35 (s, 3H), 2.58 (s, 3H), 2.85-2.95 (m, 1H), 7.30(s, 1H), 7.45 (s, 1H), 12.8-13.2 (br s, 1H). LCMS(ES) [M+H]⁺ 299.9.

c)5-Bromo-3-(sec-butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

To a stirred solution of5-bromo-3-(sec-butyl(methyl)amino)-2-methylbenzoic acid (500 mg, 1.666mmol), EDC (479 mg, 2.498 mmol), and HOBT (383 mg, 2.498 mmol) indimethyl sulfoxide (DMSO) (40 mL) was added N-methylmorpholine (0.732mL, 6.66 mmol), followed by3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (377 mg,1.999 mmol). The reaction mixture was stirred at 25° C. for 16 h. Thereaction mixture was poured onto ice water (50 mL), stirred for 10 min,allowed to stand for 10 min, and then filtered. The collected solid wasrinsed with water (50 mL), followed by 10% MeOH/ice water (50 mL) anddiethyl ether (25 mL). The contents were filtered and dried to afford400 mg of crude product. The product was purified by silica gelchromatography (eluent: 100% EtOAc) to afford the title compound (200mg, 27% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.83 (t, 3H, J=7.5 Hz), 0.96 (d, 3H, J=6.4 Hz), 1.41-1.49 (m, 1H),1.51-1.57 (m, 1H), 2.11 (s, 6H), 2.18 (s, 3H), 2.53 (s, 3H), 2.90-2.96(m, 1H), 4.23 (d, 2H, J=4.9 Hz), 5.85 (s, 1H), 6.99 (s, 1H), 7.14 (s,1H), 8.17 (t, 1H, J=4.9 Hz), 11.5 (s, 1H). LCMS(ES) [M+H]⁺ 434.5.

Example 173-(sec-Butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(2-methoxythiazol-5-yl)-2-methylbenzamide

A stirred solution of5-bromo-3-(sec-butyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(500 mg, 1.151 mmol) and 2-methoxy-5-(tributylstannyl)thiazole (465 mg,1.151 mmol) in toluene (15 mL) was degassed with argon for 20 min andthen Pd(Ph₃P)₄ (13.30 mg, 0.012 mmol) was added. The reaction mixturewas heated to 120° C. for 16 h in a sealed tube. The reaction mixturewas concentrated under reduced pressure. The crude residue was purifiedby silica gel chromatography (eluent: 3% MeOH/DCM) to afford the titlecompound (130 mg, 24% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.84 (t, 3H, J=7.4 Hz), 0.98 (d, 3H, J=6.4 Hz), 1.41-1.48 (m, 1H),1.53-1.59 (m, 1H), 2.11 (s, 3H), 2.16 (s, 3H), 2.20 (s, 3H), 2.58 (s,3H), 2.92-2.97 (m, 1H), 4.03 (s, 3H), 4.26 (d, 2H, J=4.9 Hz), 5.86 (s,1H), 6.99 (d, 1H, J=1.8 Hz), 7.12 (s, 1H), 7.58 (s, 1H), 8.14 (t, 1H,J=4.9 Hz), 11.5 (s, 1H). LCMS(ES) [M+H]⁺ 469.3.

Example 185-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpyrrolidin-1-yl)benzamide

a) 5-bromo-2-methyl-3-(2-methylpyrrolidin-1-yl)benzoic acid

To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.5 g,2.048 mmol) in methanol (20 mL) was added 5-chloropentan-2-one (3.0 ml,26.3 mmol), followed by zinc chloride (0.85 g, 6.24 mmol). The reactionwas stirred at room temperature for 2 h, then treated with sodiumcyanoborohydride (0.7 g, 11.14 mmol) portionwise (gas evolution). Thereaction was heated to 40° C. and stirred for 4 h, then heated to reflux(80° C. oil bath) and stirred overnight. LCMS showed only cyclizedproduct (92%). The reaction was evaporated to dryness, taken up inEtOAc, washed with aq. NH₄Cl, 1 N Na₂CO₃, brine, dried (Na₂SO₄),filtered, and evaporated to dryness. Purification by silica gelchromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) gave theintermediate methyl ester (0.65 g, 2.0 mmol) as a light beige oil.

The ester was taken up in MeOH (15 mL) then treated with 6 N NaOH (5 ml,30.0 mmol). The reaction was heated to reflux (80° C. oil bath) andstirred for 2 h. LCMS showed that the reaction was complete. Thereaction was cooled to room temperature then acidified with 6 N HCl (5mL). The organic solvents were removed by evaporation under vacuum. Theremaining slurry was diluted with cold water, filtered, washed with coldwater, and dried under vacuum to give5-bromo-2-methyl-3-(2-methylpyrrolidin-1-yl)benzoic acid (0.52 g, 1.744mmol, 85% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.12 (br. s., 1 H), 7.41 (d, J=2.0 Hz, 1 H), 7.23 (d, J=2.0 Hz, 1 H),3.74-3.59 (m, 1 H), 3.55-3.45 (m, 1 H), 2.69 (td, J=4.0, 8.7 Hz, 1 H),2.28 (s, 3 H), 2.20-2.08 (m, 1 H), 1.88 (tt, J=4.1, 7.7 Hz, 1 H),1.83-1.67 (m, 1 H), 1.51 (dq, J=8.9, 11.9 Hz, 1 H), 0.92 (d, J=5.8 Hz, 3H). MS(ES)+ m/e 298.1 [M+H]⁺.

b)5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpyrrolidin-1-yl)benzamide

To a mixture of 5-bromo-2-methyl-3-(2-methylpyrrolidin-1-yl)benzoic acid(250 mg, 0.838 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (160 mg, 0.848 mmol) and HOAt (110 mg, 0.808 mmol) indichloromethane (DCM) (15 mL) was added N-methylmorpholine (100 μL,0.910 mmol), followed by EDC free base (150 mg, 0.966 mmol). Thereaction was stirred at room temperature for 18 h. LCMS showed that thereaction was complete. The reaction was concentrated under vacuum thenpurified by silica gel chromatography (Analogix, SF25-40 g, 0 to 4% MeOHin CH₂Cl₂) to give 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpyrrolidin-1-yl)benzamide(323 mg, 0.747 mmol, 89% yield), after trituration with 20% CH₂Cl₂ inhexanes, filtration, and drying under vacuum as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ=11.48 (s, 1 H), 8.22 (t, J=4.8 Hz, 1 H), 7.07(d, J=2.0 Hz, 1 H), 6.93 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.24 (d,J=5.1 Hz, 2 H), 3.70-3.58 (m, 1 H), 3.53-3.44 (m, 1 H), 2.70 (td, J=3.8,8.7 Hz, 1 H), 2.19 (s, 3 H), 2.17-2.12 (m, 1 H), 2.11 (s, 3 H), 2.08 (s,3 H), 1.92-1.80 (m, 1 H), 1.80-1.68 (m, 1 H), 1.56-1.43 (m, 1 H), 0.92(d, J=5.8 Hz, 3 H). MS(ES)+ m/e 432.2 [M+H]⁺.

Example 195-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpiperidin-1-yl)benzamide

a) 5-Bromo-2-methyl-3-(2-methylpiperidin-1-yl)benzoic acid

To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.5 g,2.048 mmol) in methanol (20 mL) was added 6-chlorohexan-2-one (3.5 ml,26.5 mmol), followed by zinc chloride (0.85 g, 6.24 mmol). The reactionwas stirred at room temperature for 2 h. The reaction was treated withsodium cyanoborohydride (0.7 g, 11.14 mmol) portionwise (gas evolution)then heated to 40° C. and stirred overnight for 18 h. The reaction wasthen heated to reflux (80° C. oil bath) and stirred overnight. Thereaction was evaporated to dryness, taken up in EtOAc, washed with aq.NH₄Cl, 1 N Na₂CO₃, brine, dried (Na₂SO₄), filtered, and evaporated todryness. Purification by silica gel chromatography (Analogix, SF25-60 g,0 to 10% EtOAc in hexanes) gave the crude methyl ester (0.59 g) as alight orange oil, contaminated with some UV negative material (mostlikely the excess 6-chlorohexan-2-one).

The crude ester was taken up in MeOH (12 mL) and THF (4 mL), thentreated with 6 N NaOH (5 ml, 30.0 mmol). The reaction was heated toreflux for 2 h. The reaction was cooled to RT then acidified with 6 NHCl (5 mL). The organic solvents were removed by evaporation undervacuum. The remaining slurry was diluted with cold water, filtered,washed with cold water, and dried under vacuum to give5-bromo-2-methyl-3-(2-methylpiperidin-1-yl)benzoic acid (0.40 g, 1.281mmol, 62.5% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.15 (br. s., 1 H), 7.59 (d, J=2.0 Hz, 1 H), 7.44 (s, 1 H), 3.12-2.97(m, 1 H), 2.85 (d, J=11.1 Hz, 1 H), 2.50-2.43 (m, 1 H), 2.38 (s, 3 H),1.83-1.67 (m, 2 H), 1.66-1.53 (m, 2 H), 1.51-1.26 (m, 2 H), 0.76 (d,J=6.3 Hz, 3 H). MS(ES)+ m/e 312.1 [M+H]⁺.

b)5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpiperidin-1-yl)benzamide

To a mixture of 5-bromo-2-methyl-3-(2-methylpiperidin-1-yl)benzoic acid(250 mg, 0.801 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (160 mg, 0.848 mmol) and HOAt (110 mg, 0.808 mmol) indichloromethane (DCM) (15 mL) was added N-methylmorpholine (100 μL,0.910 mmol), followed by EDC free base (150 mg, 0.966 mmol). Thereaction was stirred at room temperature for 18 h. LCMS showed that thereaction was complete. The reaction was concentrated under vacuum thenpurified by silica gel chromatography (Analogix, SF25-40 g, 0 to 4% MeOHin CH₂Cl₂) to give5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(2-methylpiperidin-1-yl)benzamide(268 mg, 0.600 mmol, 75.0% yield), after trituration with 20% CH₂Cl₂ inhexanes, filtration, and drying under vacuum as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ=11.48 (s, 1 H), 8.23 (t, J=4.9 Hz, 1 H), 7.26(d, J=1.8 Hz, 1 H), 7.09 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.24 (d,J=5.1 Hz, 2 H), 3.08-2.96 (m, 1 H), 2.84 (d, J=11.4 Hz, 1 H), 2.49-2.39(m, 1 H), 2.18 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.81-1.66 (m, 2H), 1.64-1.52 (m, 2 H), 1.48-1.25 (m, 2 H), 0.77 (d, J=6.1 Hz, 3 H).MS(ES)+ m/e 446.3 [M+H]⁺.

Example 205-Bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

a) 3-Amino-5-bromo-2-methylbenzoic acid

To a mechanically stirred mixture of 5-bromo-2-methyl-3-nitrobenzoicacid (4.0 g, 15.38 mmol) and ammonium chloride (8.0 g, 149.6 mmol) inethanol (80 mL) and water (80 mL) was added iron powder (2.8 g, 50.1mmol). The reaction mixture was heated to reflux (70° C. oil bath) andstirred for 18 hr. The reaction mixture was diluted with EtOH (80 mL),filtered through a pad of Celite, washed with EtOH (40 mL) andevaporated to near dryness under vacuum. The remaining brown residue wastriturated with a small volume of water, filtered, washed with coldwater, and dried under vacuum to give 3-amino-5-bromo-2-methylbenzoicacid (2.70 g, 11.7 mmol, 76% yield) as a beige solid. ¹H NMR (400 MHz,MeOH-d₄) δ=7.16 (br. s., 1 H), 7.00 (br. s., 1 H), 2.26 (br. s., 3 H).MS(ES)+ m/e 230.0 [M+H]⁺.

b) 5-Bromo-3-hydroxy-2-methylbenzoic acid

To a stirred suspension of 3-amino-5-bromo-2-methylbenzoic acid (1.0 g,4.35 mmol) in 10% H₂SO₄ (10 mL) at 0° C. in an ice bath was addeddropwise a solution of sodium nitrite (0.300 g, 4.35 mmol) in water (2.0mL). The reaction mixture was stirred for 1 hr. A solution of 50% H₂SO₄in water (10 mL) was added and the reaction mixture was heated to 100°C. and stirred for 1 hr. The reaction mixture was poured into ice water(100 mL), stirred for 30 minutes, filtered, washed with water, and driedunder vacuum to give 5-bromo-3-hydroxy-2-methylbenzoic acid (0.65 g,2.81 mmol, 64.9% yield) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.10 (br. s., 1 H), 10.17 (s, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.11 (d,J=2.0 Hz, 1 H), 2.25 (s, 3 H). MS(ES)+ m/e 230.9 [M+H]⁺.

c) Methyl 5-bromo-3-(sec-butoxy)-2-methylbenzoate

To methanol (20 mL) with stirring at 0° C. in an ice bath was addeddropwise thionyl chloride (0.65 mL, 8.91 mmol). The reaction mixture wasstirred for 10 minutes, then 5-bromo-3-hydroxy-2-methylbenzoic acid(0.40 g, 1.731 mmol) was added. The reaction mixture was allowed to warmto room temperature and stirred overnight. The reaction mixture wasevaporated to dryness. Re-evaporation from toluene gave the crude methylester as a yellow-orange solid. The ester was taken up inN,N-Dimethylformamide (DMF) (10 mL) and treated with cesium carbonate(0.7 g, 2.148 mmol), followed by 2-iodobutane (0.28 mL, 2.431 mmol). Thereaction mixture was stirred at room temperature over the weekend.Another 0.50 g of cesium carbonate and 0.20 mL 2-iodobutane were addedand the reaction stirred for another 18 hrs at 40° C. The reactionmixture was evaporated to dryness, taken up in EtOAc, washed with water,brine, dried (MgSO4), filtered, and evaporated to dryness. Purificationby silica gel (Analogix, SF25-40 g, 0 to 10% EtOAc in hexanes) gavemethyl 5-bromo-3-(sec-butoxy)-2-methylbenzoate (0.35 g, 1.162 mmol,67.1% yield) as a clear oil. ¹H NMR (400 MHz, CHCl₃-d) δ=7.53 (d, J=1.8Hz, 1 H), 7.09 (d, J=2.0 Hz, 1 H), 4.30 (sxt, J=6.0 Hz, 1 H), 3.90 (s, 3H), 2.37 (s, 3 H), 1.85-1.61 (m, 2 H), 1.32 (d, J=6.1 Hz, 3 H), 1.00 (t,J=7.5 Hz, 3 H). MS(ES)+ m/e 301.1 [M+H]⁺.

d) 5-Bromo-3-(sec-butoxy)-2-methylbenzoic acid

To a stirred solution of methyl 5-bromo-3-(sec-butoxy)-2-methylbenzoate(350 mg, 1.162 mmol) in methanol (20 mL) was added 1 N NaOH (5.0 mL,5.00 mmol). The reaction mixture was stirred at 60° C. for 2 hr. Thereaction mixture was acidified with 1 N HCl (5 mL) and concentrated tonear dryness under vacuum. The remaining suspension was triturated withwater, filtered, and dried under vacuum to give5-bromo-3-(sec-butoxy)-2-methylbenzoic acid (340 mg, 1.184 mmol, 102%yield (existence of residual solvent or small amount of impurities)) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ =13.22 (br. s., 1 H), 7.40(d, J=1.8 Hz, 1 H), 7.32 (d, J=1.8 Hz, 1 H), 4.50 (sxt, J=5.9 Hz, 1 H),2.26 (s, 3 H), 1.74-1.55 (m, 2 H), 1.22 (d, J=5.8 Hz, 3 H), 0.93 (t,J=7.3 Hz, 3 H). MS(ES)+ m/e 287.0 [M+H]⁺.

e)5-Bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

To a mixture of 5-bromo-3-(sec-butoxy)-2-methylbenzoic acid (335 mg,1.167 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloridesalt (242 mg, 1.283 mmol) and HOAt (159 mg, 1.167 mmol) indichloromethane (DCM) (15 mL) was added N-methylmorpholine (0.141 mL,1.283 mmol) followed by EDC free base (217 mg, 1.400 mmol). The reactionmixture was stirred at RT for 3 hr. The reaction mixture wasconcentrated under vacuum then purified by silica gel chromatography(Analogix, SF25-40 g, 0 to 5% MeOH in CH₂Cl₂; loaded as a suspension inCH₂Cl₂) to give5-bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(346 mg, 0.821 mmol, 70.4% yield) as a white solid, after triturationwith 5% MeOH in water, filtration, and drying under vacuum. ¹H NMR (400MHz, DMSO-d₆) δ=11.47 (br. s., 1 H), 8.24 (t, J=4.9 Hz, 1 H), 7.15 (d,J=1.8 Hz, 1 H), 6.92 (d, J=1.8 Hz, 1 H), 5.86 (s, 1 H), 4.45 (sxt, J=5.9Hz, 1 H), 4.24 (d, J=5.1 Hz, 2 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 2.04(s, 3 H), 1.70-1.52 (m, 2 H), 1.21 (d, J=6.1 Hz, 3 H), 0.92 (t, J=7.5Hz, 3 H). MS(ES)+ m/e 421.2 [M+H]⁺ .

Example 215-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide

a) Methyl 5-bromo-3-isopropoxy-2-methylbenzoate

To methanol (20 mL) with stirring at 0° C. in an ice bath was addeddropwise thionyl chloride (0.65 mL, 8.91 mmol). The reaction mixture wasstirred for 10 minutes, then 5-bromo-3-hydroxy-2-methylbenzoic acid(0.40 g, 1.731 mmol) was added. The reaction mixture was allowed to warmto room temperature and stirred overnight. The reaction mixture wasevaporated to dryness. Re-evaporation from toluene gave the crude methylester as a beige solid. The ester was taken up in N,N-dimethylformamide(DMF) (10 mL) and treated with cesium carbonate (0.7 g, 2.148 mmol),followed by 2-iodopropane (0.28 mL, 2.63 mmol). The reaction mixture wasstirred at 40° C. for 18 hr. The reaction mixture was evaporated todryness, taken up in EtOAc, washed with water, brine, dried (MgSO₄),filtered, and evaporated to dryness. Purification by silica gel(Analogix, SF25-40 g, 0 to 10% EtOAc in hexanes) gave methyl5-bromo-3-isopropoxy-2-methylbenzoate (0.45 g, 1.567 mmol, 91% yield) asa clear oil. ¹H NMR (400 MHz, CHCl₃-d) δ=7.54 (d, J=2.0 Hz, 1 H), 7.11(d, J=2.0 Hz, 1 H), 4.58-4.44 (m, 1 H), 3.90 (s, 3 H), 2.36 (s, 3 H),1.37 (d, J=6.1 Hz, 6 H). MS(ES)+ m/e 287.0 [M+H]⁺.

b) 5-Bromo-3-isopropoxy-2-methylbenzoic acid

To a stirred solution of methyl 5-bromo-3-isopropoxy-2-methylbenzoate(450 mg, 1.567 mmol) in methanol (20 mL) was added 1 N NaOH (5.0 mL,5.00 mmol). The reaction mixture was stirred at 60° C. for 2 hr. Thereaction mixture was acidified with 1N HCl (5 mL) and concentrated tonear dryness under vacuum. The remaining suspension was triturated withwater, filtered, and dried under vacuum to give5-bromo-3-isopropoxy-2-methylbenzoic acid (440 mg, 1.611 mmol, 103%yield (existence of residual solvent or small amount of impurities)) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=13.26 (br. s., 1 H), 7.40 (d,J=2.0 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 4.68 (spt, J=6.0 Hz, 1 H), 2.25(s, 3 H), 1.27 (d, J=6.1 Hz, 6 H). MS(ES)+ m/e 273.0 [M+H]⁺.

c)5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide

To a mixture of 5-bromo-3-isopropoxy-2-methylbenzoic acid (430 mg, 1.574mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride salt(327 mg, 1.732 mmol) and HOAt (214 mg, 1.574 mmol) in dichloromethane(DCM) (15 mL) was added N-methylmorpholine (0.190 mL, 1.732 mmol),followed by EDC free base (293 mg, 1.889 mmol). The reaction mixture wasstirred at RT for 3 hr. The reaction mixture was concentrated undervacuum then purified by silica gel chromatography (Analogix, SF25-40 g,0 to 5% MeOH in CH₂Cl₂; loaded as a suspension in CH₂Cl₂) to give5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide (334 mg, 0.820 mmol, 52.1% yield) as a white solid,after trituration with water, filtration, and drying under vacuum. ¹HNMR (400 MHz, DMSO-d₆) δ=11.48 (br. s., 1 H), 8.24 (t, J=4.9 Hz, 1 H),7.17 (d, J=1.8 Hz, 1 H), 6.93 (d, J=1.8 Hz, 1 H), 5.86 (s, 1 H), 4.64(dt, J=6.0, 12.1 Hz, 1 H), 4.24 (d, J=5.1 Hz, 2 H), 2.18 (s, 3 H), 2.11(s, 3 H), 2.03 (s, 3 H), 1.26 (d, J=5.8 Hz, 6 H). MS(ES)+ m/e 407.1[M+H]⁺.

Example 223-[Acetyl(1-methylpropyl)amino]-5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide

a) Methyl 3-[acetyl(1-methylpropyl)amino]-5-bromo-2-methylbenzoate

To methyl 5-bromo-3-(sec-butylamino)-2-methylbenzoate (0.50 g, 1.666mmol) was added acetic anhydride (10 ml, 106 mmol). The reaction wasstirred and heated at 100° C. for 18 hr. LCMS showed that the reactionwas complete. The reaction was evaporated to dryness under vacuum.Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 40%EtOAc in hexanes) to give the product methyl5-bromo-3-(N-(sec-butyl)acetamido)-2-methylbenzoate (0.57 g, 1.666 mmol,100% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) (amide rotomers)δ=7.98 and 7.95 (2d, J=2.0 Hz, 1 H), 7.69 and 7.57 (2d, J=2.0 Hz, 1 H),4.53-4.45 and 4.30-4.23 (2m, 1 H), 3.86 (s, 3 H), 2.31 and 2.29 (2s, 3H), 1.68-1.62 and 1.52-1.44 (2m, 1 H), 1.60 and 1.14 (2d, J=6.6 Hz, 3H), 1.43-1.31 and 1.03-0.94 (2m, 1 H), 0.89 and 0.80 (2t, J=7.5 Hz, 3H). MS(ES) [M+H]⁺ 342.1.

b) 3-[Acetyl(1-methylpropyl)amino]-5-bromo-2-methylbenzoic acid

To a stirred solution of methyl5-bromo-3-(N-(sec-butyl)acetamido)-2-methylbenzoate (0.55 g, 1.607 mmol)in methanol (15 mL) was added 6 N sodium hydroxide (2.0 mL, 12.00 mmol).The reaction was stirred at 60° C. for 2 hr. LCMS showed that thereaction was complete. The reaction was acidified with 6 N HCl (2 mL)then evaporated to remove methanol. The remaining was diluted withwater, extracted with CH₂Cl₂, dried (MgSO₄), filtered, and evaporated todryness. Re-evaporation from hexanes gave the product5-bromo-3-(N-(sec-butyl)acetamido)-2-methylbenzoic acid (0.50 g, 1.523mmol, 95% yield) as a white solid foam. ¹H NMR (400 MHz, DMSO-d₆) (amiderotomers) δ=13.46 (br. s., 1 H), 7.95 and 7.93 (2d, J=2.0 Hz, 1 H), 7.64and 7.52 (2d, J=2.0 Hz, 0 H), 4.49 and 4.24 (2dq, J=6.8, 14.1 Hz, 1 H),2.32 and 2.30 (2s, 3 H), 1.70-1.60 and 1.54-1.43 (2m, 1 H), 1.60-1.14(2d, J=6.6 Hz, 3 H), 1.43-1.24 and 1.06-0.94 (2m, 1 H), 0.89 and 0.80(2t, J=7.3 Hz, 3 H). MS(ES) [M+H]⁺ 328.1.

c)3-[Acetyl(1-methylpropyl)amino]-5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide

To a mixture of 5-bromo-3-(N-(sec-butyl)acetamido)-2-methylbenzoic acid(250 mg, 0.762 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (160 mg, 0.848 mmol) and HOAt (110 mg, 0.808 mmol) inDichloromethane (DCM) (15 mL) was added N-methylmorpholine (100 μL,0.910 mmol) followed by EDC free base (150 mg, 0.966 mmol). The reactionwas stirred at room temperature for 4 hr. LCMS showed that the reactionwas complete. The reaction was concentrated under vacuum then purifiedby silica gel chromatography (Analogix, SF25-60 g, 0 to 5% MeOH inCH₂Cl₂) to give the product5-bromo-3-(N-(sec-butypacetamido)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(310 mg, 0.670 mmol, 88% yield), after trituration with 10% CH₂Cl₂ inhexanes, filtration, and drying under vacuum as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) (amide rotomers) δ=11.51 (br. s., 1 H), 8.45 (q,J=5.1 Hz, 1 H), 7.43 (td, J=2.0, 7.6 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H),5.87 (s, 1 H), 4.49-4.41 and 4.20-4.16 (2m, 1 H), 4.26 (d, J=4.8 Hz, 2H), 2.20 (s, 3 H), 2.12 (s, 3 H), 2.09 and 2.07 (2s, 3 H), 1.13 and 0.80(2d, J=6.82, 3 H), 0.89 and 0.81 (2t, J=7.4, 3H). MS(ES) [M+H]⁺ 462.2.

Example 232,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylpropyl)amino]benzamide

a) Methyl 3-amino-2,5-dichlorobenzoate

To methanol (50 mL) with stirring at 0° C. was slowly added thionylchloride (4.0 mL, 54.8 mmol) dropwise. After stirring for 15 minutes3-amino-2,5-dichlorobenzoic acid (2.5 g, 12.13 mmol) was added. Thereaction was allowed to warm to RT and stirred for 24 hr. LCMS showedthat the reaction was 59% complete. The reaction was heated to reflux(70° C. oil bath) and stirred for 5 hr. LCMS now showed that thereaction was complete. The reaction was evaporated to dryness, taken upin EtOAc, washed with 1N Na₂CO₃, brine, dried (Na₂SO₄), filtered andevaporated to dryness to give the product methyl3-amino-2,5-dichlorobenzoate (2.63 g, 11.95 mmol, 98% yield) as a beigeoil (solidified under vacuum). ¹H NMR (400 MHz, DMSO-d₆) δ=6.98 (d,J=2.5 Hz, 1 H), 6.88 (d, J=2.5 Hz, 1 H), 5.99 (s, 2 H), 3.83 (s, 3 H).MS(ES) [M+H]⁺220.0.

b) Methyl 2,5-dichloro-3-[(1-methylpropyl)amino]benzoate

In a 20 mL microwave vial was added methyl 3-amino-2,5-dichlorobenzoate(500 mg, 2.272 mmol), DIEA (0.5 mL, 2.86 mmol), 2-iodobutane (1.0 mL,8.68 mmol) and Dimethyl Sulfoxide (DMSO) (0.5 mL). The vial was cappedand stirred at 100° C. for 24 hr. LCMS showed 36% product and 19%starting material (45% of an unknown). Purification by silca gelchromatography (Analogix, SF25-60 g, 0 to 15% EtOAc in hexanes) gave theproduct methyl 3-(sec-butylamino)-2,5-dichlorobenzoate (180 mg, 0.652mmol, 28.7% yield) as a clear oil. LCMS showed that it was 91% pure.H-NMR was messy (˜70% pure). Used as is in the next reaction. ¹H NMR(400 MHz, DMSO-d₆) δ =6.91 (d, J=2.5 Hz, 1 H), 6.88 (d, J=2.3 Hz, 1 H),5.33 (d, J=8.6 Hz, 1 H), 3.84 (s, 3 H), 3.57-3.49 (m, 1 H), 1.60 (dq,J=6.9, 14.1 Hz, 1 H), 1.55-1.44 (m, 1 H), 1.14 (d, J=6.3 Hz, 3 H), 0.89(t, J=7.5 Hz, 3 H). MS(ES) [M+H]⁺ 276.1.

c)2,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylpropyl)amino]benzamide

To a stirred solution of methyl 3-(sec-butylamino)-2,5-dichlorobenzoate(180 mg, 0.652 mmol) in methanol (15 mL) was added 1N sodium hydroxide(2.5 mL, 2.500 mmol). The reaction was stirred at room temperature overthe weekend. LCMS showed that the reaction was complete. The reactionwas evaporated under vacuum to remove the methanol then acidified with1N HCl (2.5 mL). The sticky solid that separated was extracted withCH₂Cl₂, dried (MgSO₄), filtered and concentrated under vacuum to givethe crude carboxylic acid.

To a stirred mixture of the above acid,3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride salt (135mg, 0.717 mmol) and HOAt (90 mg, 0.661 mmol) in Dichloromethane (DCM)(20 mL) was added N-methylmorpholine (80 μl, 0.728 mmol) followed by EDCfree base (125 mg, 0.805 mmol). The reaction was stirred at roomtemperature overnight for 18 hr. LCMS showed that the reaction wascomplete. The reaction was concentrated under vacuum and purifed bysilica gel chromatography (Analogix, SF25-80 g, 0 to 4% MeOH in CH₂Cl₂).TLC of the fractions showed a very closely eluting lower spot whichpartially separated out. The fractions containing what appeared as purewere combined, evaporated to dryness, triturated with hexanes, filtered,and dried under vacuum to give the product as a white solid. LCMS showeda very closely eluting impurity that did not separate (˜70% pure). Thiscrude product was re-purified by preparative chiral HPLC on a ChiralcelOJ-H, 5 microns (30 mm×250 mm) column eluted with (80:20) n-heptane,ethanol. Carried out 10 prep runs. Collected the pure product fractionsand evaporated under vacuum at 50° C. to a constant weight. The product3-(sec-butylamino)-2,5-dichloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide(119 mg, 0.30 mmol, 46.0% yield) was obtained as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=11.48 (s, 1 H), 8.33 (t, J=4.9 Hz, 1 H), 6.74 (d,J=2.3 Hz, 1 H), 6.48 (d, J=2.3 Hz, 1 H), 5.86 (s, 1 H), 5.12 (d, J=8.6Hz, 1 H), 4.24 (d, J=5.1 Hz, 2 H), 3.54-3.43 (m, 1 H), 2.18 (s, 3 H),2.11 (s, 3 H), 1.65-1.53 (m, 1 H), 1.53-1.42 (m, 1 H), 1.13 (d, J=6.3Hz, 3 H), 0.88 (t, J=7.3 Hz, 3 H). MS(ES) [M+H]⁺ 396.1.

Example 242,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylethyl)oxy]benzamide

a) 2,5-Dichloro-3-iodobenzoic acid

To a stirred solution of iodine (4.84 g, 19.08 mmol) in DMSO (9.0 mL)was added t-butylnitrite (3.4 ml, 28.6 mmol). A solution of3-amino-2,5-dichlorobenzoic acid (3.93 g, 19.08 mmol) in DMSO (13 mL)was then added slowly dropwise to the above. Exothermic (Do not let thetemperature rise above 50° C.). Stopped halfway through to let thereaction cool down. (Saw gas evolution during addition.) The reactionwas allowed to stir overnight at room temperature. The reaction waspoured into water and extracted with EtOAc (2×). The EtOAc phases werecombined and washed with an aqueous solution of sodium bisulfite, water,dried (MgSO₄), filtered, and evaporated to dryness to give the product2,5-dichloro-3-iodobenzoic acid (5.38 g, 16.98 mmol, 89% yield) as aorange brown solid. The product was 80% pure by LCMS and was used as isin the next reaction. ¹H NMR (400 MHz, DMSO-d₆) δ=13.92 (br. s., 1 H),8.21 (d, J=2.5 Hz, 1 H), 7.79 (d, J=2.5 Hz, 1 H). MS(ES) [M+H]⁺ 316.9.

b) 2,5-Dichloro-3-hydroxybenzoic acid

To a flask containing water (100 mL) was added sodium hydroxide (9.7 g,243 mmol). After the sodium hydroxide was completely dissolved,2,5-dichloro-3-iodobenzoic acid (5.0 g, 15.78 mmol) was added followedby copper(II) sulfate pentahydrate (2.6 g, 10.41 mmol). The reaction washeated to 100° C. and stirred for 3 hr. LCMS showed that the reactionwas mostly complete. The dark reaction was cooled in an ice bath andacidified with conc. HCl (˜20 mL). The mixture was extracted with EtOAc,filtered to remove a small amount of insoluble material, washed withwater, aq. sodium bisulfite, brine, dried (MgSO₄), filtered andevaporated to dryness to give the product 2,5-dichloro-3-hydroxybenzoicacid (3.26 g, 9.76 mmol, 61.9% yield) (62% pure by LCMS) as a orangebrown solid. This crude was used as is and was purified in the nextstep. ¹H NMR (400 MHz, DMSO-d₆) δ=13.59 (br. s., 1 H), 11.02 (s, 1 H),7.18 (d, J=2.5 Hz, 1 H), 7.10 (d, J=2.5 Hz, 1 H). MS(ES) [M+H]⁺206.9.

c) Methyl 2,5-dichloro-3-hydroxybenzoate

To methanol (100 mL) with stirring at 0° C. was slowly added thionylchloride (8.0 mL, 110 mmol) dropwise. After stirring for 15 minutes2,5-dichloro-3-hydroxybenzoic acid (3.25 g, 15.70 mmol) was added. Thereaction was allowed to warm to room temperature and stirred for 24 hr.LCMS showed that the reaction was complete. The reaction was evaporatedto dryness. Purified by silica gel chromatography (Analogix, SF40-120 g,0 to 10% EtOAc in hexanes) (Did not dissolve well in CH₂Cl₂) to give thecrude product, which was triturated with hexanes to remove most of theorange color, and dried to give the product methyl2,5-dichloro-3-hydroxybenzoate (1.83 g, 8.28 mmol, 52.7% yield) as alight orange solid. The colored impurity was removed in the next step.¹H NMR (400 MHz, DMSO-d₆) δ=11.14 (s, 1 H), 7.23 (d, J=2.5 Hz, 1 H),7.15 (d, J=2.5 Hz, 1 H), 3.85 (s, 3 H). MS(ES) [M+H]⁺ 221.0.

d) Methyl 2,5-dichloro-3-[(1-methylethyl)oxy]benzoate

To a stirred mixture of methyl 2,5-dichloro-3-hydroxybenzoate (0.6 g,2.71 mmol) and cesium carbonate (1.1 g, 3.38 mmol) inN,N-Dimethylformamide (DMF) (10 mL) was added 2-iodopropane (0.44 mL,4.40 mmol). The reaction was stirred overnight at room temperature. LCMSshowed that the reaction was complete. The reaction was evaporated todryness, taken up in EtOAc, washed with water, brine, dried (MgSO₄),filtered and concentrated under vacuum, Purified by silica gelchromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) to givethe product methyl 2,5-dichloro-3-isopropoxybenzoate (0.72 g, 2.74 mmol,101% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ=7.49 (d, J=2.5Hz, 1 H), 7.35 (d, J=2.3 Hz, 1 H), 4.81 (dt, J=6.0, 11.9 Hz, 1 H), 3.86(s, 3 H), 1.30 (d, J=6.1 Hz, 6 H). MS(ES) [M+H]⁺ 263.0.

e) 2,5-Dichloro-3-[(1-methylethyl)oxy]benzoic acid

To a stirred solution of methyl 2,5-dichloro-3-isopropoxybenzoate (0.7g, 2.66 mmol) in methanol (30 mL) was added 1N sodium hydroxide (10 ml,10.00 mmol). The reation was heated to 40° C. and stirred for 18 hr.LCMS showed that the reaction was complete. The reaction wasconcentrated under vacuum to remove the methanol then acidified with 1NHCl (10 mL). The precipitated solid was triturated, filtered, washedwith water and dried under vacuum to give the product2,5-dichloro-3-isopropoxybenzoic acid (643 mg, 2.58 mmol, 97% yield) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=13.69 (br. s., 1 H),7.43 (d, J=2.3 Hz, 1 H), 7.29 (d, J=2.5 Hz, 1 H), 4.80 (dt, J=6.0, 12.1Hz, 1 H), 1.30 (d, J=6.1 Hz, 6 H). MS(ES) [M+H]⁺ 249.0.

f)2,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(1-methylethyl)oxy]benzamide

To a stirred mixture of 2,5-dichloro-3-isopropoxybenzoic acid (250 mg,1.004 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloridesalt (220 mg, 1.166 mmol) and HOAt (137 mg, 1.004 mmol) inDichloromethane (DCM) (20 mL) was added N-methylmorpholine (130 μL,1.182 mmol) followed by EDC free base (210 mg, 1.353 mmol). The reactionwas stirred at room temperature overnight for 18 hr. LCMS showed thatthe reaction was complete. The reaction was concentrated under vacuumand purifed by silica gel chromatography (Analogix, SF25-60 g, 0 to 5%MeOH in CH₂Cl₂) (Not real soluble in CH₂Cl₂.). The pure fractions werecombined, evaporated to dryness, triturated with 5% MeOH in water,filtered, washed with water and dried under vacuum to give the product2,5-dichloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxybenzamide(340 mg, 0.887 mmol, 88% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.49 (s, 1 H), 8.41 (t, J=4.9 Hz, 1 H), 7.29 (d, J=2.3 Hz, 1H), 6.93 (d, J=2.3 Hz, 1 H), 5.87 (s, 1 H), 4.76 (dt, J=6.1, 12.1 Hz, 1H), 4.25 (d, J=4.8 Hz, 2 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 1.28 (d,J=6.1 Hz, 6 H). MS(ES) [M+H]⁺ 383.1.

Example 255—Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-{[1-methyl-2-(methyloxy)ethyl}amino]benzamide

a) 5—Chloro-2-methyl-3-nitrobenzoic acid

To H₂SO₄ (250 ml, 4690 mmol) with stirring at −15° C. (NaCl ice bath)was added portionwise 5-chloro-2-methylbenzoic acid (25 g, 147 mmol)(slowly went into solution). Next a cooled mixture of fuming nitric acid(12.5 ml, 280 mmol) in H₂SO₄ (62 mL) was added dropwise. After stirringat −15° C. for 2 hr a cloudy suspension began to form. The reaction waspoured onto ice (˜500 mL) and stirred for 30 minutes. The suspension wasfiltered, washed with water, and dried under vacuum to give the product5-chloro-2-methyl-3-nitrobenzoic acid (30.58 g, 142 mmol, 97% yield) asan off-white solid. 81% pure by LCMS did not show a mass ion. Only 73%pure by NMR. Used as is in the next reaction. ¹H NMR (400 MHz, DMSO-d₆)δ=13.89 (br. s., 1 H), 8.22 (d, J=2.0 Hz, 1 H), 8.03 (d, J=2.0 Hz, 1 H),2.47 (s, 3 H).

b) Methyl 5-chloro-2-methyl-3-nitrobenzoate

To methanol (150 mL) with stirring at 0° C. was slowly added thionylchloride (18 ml, 247 mmol) dropwise. After stirring for 15 minutes5-chloro-2-methyl-3-nitrobenzoic acid (10.0 g, 46.4 mmol) was added. Thereaction was allowed to warm to room temperature and stirred for 24 hr.LCMS showed that the reaction was complete. The reaction was evaporatedto dryness. The remaining was taken up in a small volume of CH₂Cl₂. Awhite solid crashed out of solution. After trituration the insolublesolid was filtered off and rinsed with a small volume of CH₂Cl₂. Thiswhite solid corresponded to the impurity from the crude acid startingmaterial. The CH₂Cl₂ soluble filtrate was concentrated under vacuum andpurified by silica gel chromatography (Analogix, SF40-120 g, 0 to 10%EtOAc in hexanes) to give the product methyl5-chloro-2-methyl-3-nitrobenzoate (7.37 g, 32.1 mmol, 69.2% yield) as alight yellow oil (solidified to a white solid under vacuum). ¹H NMR (400MHz, DMSO-d₆) δ=8.27 (d, J=2.3 Hz, 1 H), 8.07 (d, J=2.3 Hz, 1 H), 3.89(s, 3 H), 2.45 (s, 3 H). MS(ES) [M+H]⁺ 230.0 (Very weak).

c) Methyl 3-amino-5-chloro-2-methylbenzoate

To a stirred solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (5.0g, 21.78 mmol) in ethyl acetate (150 mL) was added tin(II) chloridedihydrate (20 g, 89 mmol). The mixture was stirred and heated to reflux(85° C. oil bath) for 3 hr (clear solution). LCMS showed that thereaction was complete. The reaction was cooled to room temperature andpoured into 1N Na₂CO₃ (200 mL). The resultant suspension was stirred for30 minutes, filtered through a pad of Celite (slow! used a large filterfunnel), and rinsed with EtOAc. The filtrate was transferred to aseparatory funnel. The EtOAc phase was isolated, washed with water,brine, dried (Na₂SO₄), filtered and concentrated under vacuum.Purification by silica gel chromatography (Analogix, SF40-120 g, 0 to30% EtOAc in hexanes) gave the product methyl3-amino-5-chloro-2-methylbenzoate (4.05 g, 20.29 mmol, 93% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ=6.84 (d, J=6.7 Hz, 1 H), 6.83(d, J=6.7 Hz, 1 H), 5.47 (s, 2 H), 3.79 (s, 3 H), 2.13 (s, 3 H). MS(ES)[M+H]⁺ 200.0.

d) Methyl5-chloro-2-methyl-3-{[1-methyl-2-(methyloxy)ethyl]amino}benzoate

To a stirred mixture of methyl 3-amino-5-chloro-2-methylbenzoate (750mg, 3.76 mmol) and 1-methoxypropan-2-one (1.7 mL, 18.47 mmol) inmethanol (30 mL) was added zinc chloride (1.5 g, 11.01 mmol). Afterstirring for 2 hr sodium cyanoborohydride (1.2 g, 19.10 mmol) was addedportionwise over 30 minutes (gas evolution). The reaction was heated to40° C. and stirred overnight. LCMS showed that the reaction was 81%complete. The reaction was evaporated to dryness under vacuum, taken upin EtOAc, washed with sat. NH₄Cl, water, brine, dried (Na₂SO₄), filteredand concentrated under vacuum. Purification by silca gel chromatography(Analogix, SF25-60 g, 0 to 20% EtOAc in hexanes) gave the product methyl5-chloro-3-((1-methoxypropan-2-yl)amino)-2-methylbenzoate (0.69 g, 2.54mmol, 67.6% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ=6.85 (d,J=2.0 Hz, 1 H), 6.78 (d, J=2.0 Hz, 1 H), 4.92 (d, J=8.3 Hz, 1 H), 3.80(s, 3 H), 3.78-3.68 (m, 1 H), 3.44-3.39 (m, 1 H), 3.34-3.29 (m, 1 H),3.28 (s, 3 H), 2.15 (s, 3 H), 1.16 (d, J=6.6 Hz, 3 H). MS(ES) [M+H]⁺272.1.

e) 5—Chloro-2-methyl-3-{[1-methyl-2-(methyloxy)ethyl]amino}benzoic acid

To a stirred solution of methyl5-chloro-3-((1-methoxypropan-2-yl)amino)-2-methylbenzoate (0.65 g, 2.392mmol) in methanol (30 mL) was added 1N sodium hydroxide (10 mL, 10.00mmol). The reation was heated to 40° C. and stirred for 18 hr. LCMSshowed that the reaction was complete. The reaction was concentratedunder vacuum to remove the methanol then acidified with 1N HCl (10 mL).The precipitated gummy solid was extracted with CH₂Cl₂, washed withbrine, dried (Na₂SO₄), filtered, and evaporated to dryness to give theproduct 5-chloro-3-((1-methoxypropan-2-yl)amino)-2-methylbenzoic acid(0.62 g, 2.406 mmol, 101% yield(existence of residual solvent or smallamount of impurities)) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.02 (br. s., 1 H), 6.84 (d, J=2.0 Hz, 1 H), 6.74 (d, J=2.0 Hz, 1 H),4.86 (d, J=8.1 Hz, 1 H), 3.78-3.66 (m, 1 H), 3.45-3.37 (m, 1 H), 3.32(dd, J=5.9, 9.5 Hz, 2 H), 2.17 (s, 3 H), 1.15 (d, J=6.3 Hz, 3 H). MS(ES)[M+H]⁺ 258.1.

f)5—Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-{[1-methyl-2-(methyloxy)ethyl]amino}benzamide

To a stirred mixture of5-chloro-3-((1-methoxypropan-2-yl)amino)-2-methylbenzoic acid (400 mg,1.552 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloridesalt (300 mg, 1.590 mmol) and HOAt (215 mg, 1.580 mmol) inDichloromethane (DCM) (20 mL) was added N-methylmorpholine (0.18 mL,1.637 mmol) followed by EDC free base (290 mg, 1.868 mmol). The reactionwas stirred at room temperature overnight for 18 hr. LCMS showed thatthe reaction was complete. The reaction was concentrated under vacuumand purifed by silica gel chromatography (Analogix, SF25-60 g, 0 to 5%MeOH in CH₂Cl₂). The pure fractions were combined, evaporated todryness, triturated with hexanes, filtered, washed with hexanes anddried under vacuum to give the product5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((1-methoxypropan-2-yl)amino)-2-methylbenzamide(561 mg, 1.432 mmol, 92% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.47 (s, 1 H), 8.11 (t, J=4.9 Hz, 1 H), 6.61 (d, J=2.0 Hz, 1H), 6.43 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.72 (d, J=8.3 Hz, 1 H),4.23 (d, J=5.1 Hz, 2 H), 3.74-3.64 (m, 1 H), 3.42-3.37 (m, 1 H), 3.33(s, 3 H), 3.32-3.29 (m, 1 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 1.96 (s, 3H), 1.14 (d, J=6.3 Hz, 3 H). MS(ES) [M+H]⁺ 392.2.

Example 265—Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-[(2-hydroxy-1-methylethyl)amino]-2-methylbenzamide

To a stirred suspension of5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((1-methoxypropan-2-yl)amino)-2-methylbenzamide(250 mg, 0.638 mmol) in acetonitrile (10 mL) was added TMSI (500 μl,3.67 mmol) dropwise (the reaction quickly cleared up). The reaction washeated to 70° C. (a condensor was attached). After 1 hr LCMS showed thatthe reaction was only 39% complete. An additional 200 uL of TMSI wasadded and the reaction stirred at 70° C. for another 1 hr. LCMS nowshowed that the reaction was 55% complete. One more 200 uL of TMSI wasadded and the reaction stirred for an additional 2 hr at 70° C. Totaltime was 4 hr. A total of 900 uL TMSI (˜10 equiv.) was used. LCMS showedthat the reaction was ˜80% complete. The reaction was cooled to roomtemperature and treated with methanol (10 mL) and stirred for 10 minutesthen treated with aq. Na₂S₂O₄ (10 mL) and stirred for 20 minutes. (Thecolor eventually disappeared.) The organics were removed by evaporationunder vacuum. The insoluble material was removed by filtration, washedwith a small volume of water then dried under vacuum to give the crudeproduct. Purified by silica gel chromatography (Analogix, SF25-60 g, 0to 10% MeOH in CH₂Cl₂) (A DASi column with just a filter was used sincethe starting material was not soluble in CH₂Cl₂.) The pure fractionswere combined, evaporated to dryness, triturated with water, filteredand dried under vacuum to give the product5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((1-hydroxypropan-2-yl)amino)-2-methylbenzamide(99 mg, 0.262 mmol, 41.1% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.47 (s, 1 H), 8.11 (t, J=4.9 Hz, 1 H), 6.59 (d, J=2.0 Hz, 1H), 6.42 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.78 (br. s., 1 H), 4.68 (d,J=7.3 Hz, 1 H), 4.23 (d, J=5.1 Hz, 2 H), 3.52-3.41 (m, 2 H), 3.39-3.30(m, 1H), 2.18 (s, 3 H), 2.11 (s, 3 H), 1.97 (s, 3 H), 1.13 (d, J=6.3 Hz,3 H). MS(ES) [M+H]⁺ 378.1.

Example 275—Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)oxy]benzamide

a) Methyl 5-chloro-3-hydroxy-2-methylbenzoate

To a vigorously stirred solution of methyl5-chloro-3-hydroxy-2-methylbenzoate (1.28 g, 6.38 mmol, 70.8% yield) inmethanol (5 mL) was added dropwise 10% H₂SO₄ (20 ml, 37.5 mmol). (Thesolution quickly formed a suspension.) The stirred mixture was cooled to0° C. in an ice bath then a solution of sodium nitrite (0.80 g, 11.59mmol) in water (6 mL) was added dropwise slowly over 15 minutes. Thesuspension was stirred at 0° C. for 1 hr. Clumps were ocassionallybroken up with the aid of a spatula. After 1 hr a small volume ofmethanol (˜5 mL) was used to rinse down the sides of the flask. Thereaction was allowed to warm to room temperature then treated with asolution of 50% H₂SO₄ (20 ml, 188 mmol). The reaction was heated to 100°C. and stirred for 1 hr. (A blast shield was used for safety.) Theresulting suspension was poured into ice water (˜300 mL), the solidsfiltered off, washed with water, then dried under vacuum to give thecrude phenol. LCMS showed 22% hydrolyzed methyl ester and 76% product. Astirred solution of MeOH (100 mL) at 0° C. in an ice bath was slowlytreated with thionyl chloride (5.0 ml, 68.5 mmol). After stirring for 15minutes the solution was added to the above. The reaction was stirredovernight at room temperature. LCMS showed that all of the mixture wasconverted to the methyl ester. The reaction was evaporated to drynessthen purified by silica gel chromatography (Analogix, SF25-60 g, 0 to20% EtOAc in hexanes). The pure fractions were combined and evaporatedto dryness to give the product methyl5-chloro-3-hydroxy-2-methylbenzoate (1.28 g, 6.38 mmol, 70.8% yield) asa pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.30 (br. s., 1 H),7.18 (d, J=2.3 Hz, 1 H), 7.01 (d, J=2.0 Hz, 1 H), 3.82 (s, 3 H), 2.25(s, 3 H). MS(ES) [M+H]⁺ 201.0.

b) Methyl 5-chloro-2-methyl-3-[(1-methylethyl)oxy]benzoate

To a stirred mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.6g, 2.99 mmol) and cesium carbonate (1.2 g, 3.68 mmol) inN,N-Dimethylformamide (DMF) (10 mL) was added 2-iodopropane (0.45 mL,4.50 mmol). The reaction was stirred overnight at room temperature. LCMSshowed that the reaction was complete. The reaction was evaporated todryness, taken up in EtOAc, washed with water, brine, dried (MgSO₄),filtered and concentrated under vacuum. Purified by silica gelchromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) to givethe product methyl 5-chloro-3-isopropoxy-2-methylbenzoate (0.62 g, 2.55mmol, 85% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ=7.29 (d,J=2.0 Hz, 1 H), 7.28 (d, J=2.2 Hz, 1 H), 4.70 (dt, J=6.1, 12.1 Hz, 1 H),3.83 (s, 3 H), 2.25 (s, 3 H), 1.28 (d, J=6.1 Hz, 6 H). MS(ES) [M+H]⁺243.1.

c) 5—Chloro-2-methyl-3-[(1-methylethyl)oxy]benzoic acid

To a stirred solution of methyl 5-chloro-3-isopropoxy-2-methylbenzoate(0.60 g, 2.472 mmol) in methanol (20 mL) was added 1N sodium hydroxide(10 mL, 10.00 mmol). The reaction was heated to 40° C. and stirred for18 hr. LCMS showed that the reaction was complete. The reaction wasevaporated under vacuum to remove the methanol then acidified with 1NHCl (10 mL). The precipitated solids were filtered off, washed withwater and dried under vacuum to give the product5-chloro-3-isopropoxy-2-methylbenzoic acid (0.53 g, 2.318 mmol, 94%yield) as a white solid. This material was 93% pure by LCMS and had 7%starting ester. Used as is in the next reaction. ¹H NMR (400 MHz,DMSO-d₆) δ=13.20 (br. s., 1 H), 7.27 (d, J=2.0 Hz, 1 H), 7.23 (d, J=2.3Hz, 1 H), 4.68 (dt, J=6.0, 11.9 Hz, 1 H), 2.27 (s, 3 H), 1.28 (d, J=5.8Hz, 6 H). MS(ES) [M+H]⁺ 229.1.

d)5—Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methyl-3-[(1-methylethyl)oxy]benzamide

To a stirred mixture of 5-chloro-3-isopropoxy-2-methylbenzoic acid (250mg, 1.093 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (230 mg, 1.219 mmol) and HOAt (150 mg, 1.102 mmol) inDichloromethane (DCM) (20 mL) was added N-methylmorpholine (140 μL,1.273 mmol) followed by EDC free base (210 mg, 1.353 mmol). The reactionwas stirred at room temperature overnight for 18 hr. LCMS showed thatthe reaction was complete. The reaction was concentrated under vacuumand purifed by silica gel chromatography (Analogix, SF25-60 g, 0 to 5%MeOH in CH₂Cl₂) (Not real soluble in CH₂Cl₂. Used a DASi filter). Thepure fractions were combined, evaporated to dryness, triturated with 5%MeOH in water, filtered, washed with water and dried under vacuum togive the product5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide(338 mg, 0.932 mmol, 85% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=11.48 (s, 1 H), 8.24 (t, J=4.9 Hz, 1 H),7.07 (d, J=2.0 Hz, 1 H), 6.80 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.65(dt, J=6.0, 12.1 Hz, 1 H), 4.24 (d, J=5.1 Hz, 2 H), 2.18 (s, 3 H), 2.11(s, 3 H), 2.04 (s, 3 H), 1.26 (d, J=5.8 Hz, 6 H). MS(ES) [M+H]⁺ 363.1.

Example 285-Chloro-3-(cyclopentyloxy)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide

a) Methyl 5-chloro-3-(cyclopentyloxy)-2-methylbenzoate

To a stirred mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.6g, 2.99 mmol) and cesium carbonate (1.2 g, 3.68 mmol) inN,N-Dimethylformamide (DMF) (10 mL) was added iodocyclopentane (0.55 mL,4.76 mmol). The reaction was stirred overnight at room temperature. LCMSshowed that the reaction was 62% complete. The reaction was heated at60° C. and stirred overnight. LCMS showed that the reaction wascomplete. The reaction was evaporated to dryness, taken up in EtOAc,washed with water, brine, dried (MgSO₄), filtered and concentrated undervacuum, Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to10% EtOAc in hexanes) to give the product methyl5-chloro-3-(cyclopentyloxy)-2-methylbenzoate (0.81 g, 3.01 mmol, 101%yield(existence of residual solvent or small amount of impurities)) as aclear oil. ¹H NMR (400 MHz, DMSO-d₆) δ=7.28 (d, J=2.0 Hz, 1 H), 7.22 (d,J=2.0 Hz, 1 H), 4.94 (t, J=5.4 Hz, 1 H), 3.82 (s, 3 H), 2.24 (s, 3 H),1.96-1.85 (m, 2 H), 1.76-1.66 (m, 4 H), 1.65-1.57 (m, 2 H). MS(ES)[M+H]⁺ 269.1.

b) 5—Chloro-3-(cyclopentyloxy)-2-methylbenzoic acid

To a stirred solution of methyl5-chloro-3-(cyclopentyloxy)-2-methylbenzoate (0.80 g, 2.98 mmol) inmethanol (40 mL) was added 1N sodium hydroxide (10 ml, 10.00 mmol) . Thereaction was heated to 40° C. and stirred for 18 hr. LCMS showed thatthe reaction was complete. The reaction was evaporated under vacuum toremove the methanol then acidified with 1N HCl (10 mL). The precipitatedsolids were filtered off, washed with water and dried under vacuum togive the product 5-chloro-3-(cyclopentyloxy)-2-methylbenzoic acid (0.74g, 2.91 mmol, 98% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.24 (br. s., 1 H), 7.26 (d, J=2.3 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H),4.92 (t, J=5.6 Hz, 1 H), 2.25 (s, 3 H), 1.96-1.84 (m, 2 H), 1.77-1.65(m, 4 H), 1.65-1.54 (m, 2 H). MS(ES) [M+H]⁺ 255.1.

c)5—Chloro-3-(cyclopentyloxy)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-methylbenzamide

To a stirred mixture of 5-chloro-3-(cyclopentyloxy)-2-methylbenzoic acid(250 mg, 0.982 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (200 mg, 1.060 mmol) and HOAt (140 mg, 1.029 mmol) inDichloromethane (DCM) (20 mL) was added N-methylmorpholine (120 μL,1.091 mmol) followed by EDC free base (190 mg, 1.224 mmol). The reactionwas stirred at room temperature overnight for 18 hr. LCMS showed thatthe reaction was complete. The reaction was concentrated under vacuumand purifed by silica gel chromatography (Analogix, SF25-60 g, 0 to 4%MeOH in CH₂Cl₂) (Not real soluble in CH₂Cl₂. Used a DASi filter). Thepure fractions were combined, evaporated to dryness, triturated with 5%MeOH in water, filtered, washed with water and dried under vacuum togive the product5-chloro-3-(cyclopentyloxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(332 mg, 0.854 mmol, 87% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.48 (br. s., 1 H), 8.23 (t, J=4.9 Hz, 1 H), 7.02 (d, J=1.8Hz, 1 H), 6.80 (d, J=2.0 Hz, 1 H), 5.86 (s, 1 H), 4.89 (t, J=5.4 Hz, 1H), 4.24 (d, J=5.1 Hz, 2 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 2.02 (s, 3H), 1.93-1.83 (m, 2 H), 1.76-1.64 (m, 4 H), 1.63-1.55 (m, 2 H). MS(ES)[M+H]⁺ 389.1.

Example 292,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-(1-methyl-1H-pyrazol-5-yl)benzamide

a) Methyl 2,5-dichloro-3-iodobenzoate

To methanol (100 mL) at 0° C. with stirring was added dropwise thionylchloride (5.0 ml, 68.5 mmol). After 15 minutes2,5-dichloro-3-iodobenzoic acid (5.0 g, 15.78 mmol) was added. Thereaction was stirred overnight at room temperature then refluxed at 70°C. for 4 hr. LCMS showed that the reaction was complete. The reactionwas evaporated to dryness under vacuum then purified by silica gelchromatography (Analogix, SF40-115 g, 0 to 15% EtOAc in hexanes). Thepure fractions were combined and evaporated to dryness to give theproduct methyl 2,5-dichloro-3-iodobenzoate (4.17 g, 12.60 mmol, 80%yield) as a yellow oil (solidified under vacuum). ¹H NMR (400 MHz,DMSO-d₆) δ=8.27 (d, J=2.5 Hz, 1 H), 7.85 (d, J=2.5 Hz, 1 H), 3.87 (s, 3H). MS(ES) [M+H]⁺ 330.7 (weak).

b) Methyl 2,5-dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoate

In a 20 mL microwave vial was added methyl 2,5-dichloro-3-iodobenzoate(500 mg, 1.511 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(500 mg, 2.403 mmol), sodium bicarbonate (381 mg, 4.53 mmol),N,N-Dimethylformamide (DMF) (20 mL) and water (2 mL). The mixture wasstirred and purged with N₂. To the reaction was added PdCl₂(PPh₃)₂ (60mg, 0.085 mmol). The vial was capped and stirred at 90° C. for 2 hr. Thereaction turned black after 1.5 hrs. LCMS showed after 2 hr the reactionwas complete. The reaction was evaporated to dryness under vacuum andpurified by silica gel chromatography (Analogix, SF25-60 g, 0 to 30%EtOAc in hexanes) (loaded with CH₂Cl₂ onto a DASi column). The purefractions were combined and evaporated to dryness to give the productmethyl 2,5-dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoate (0.36 g, 1.263mmol, 84% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ=7.98 (d,J=2.8 Hz, 1 H), 7.81 (d, J=2.5 Hz, 1 H), 7.54 (d, J=1.8 Hz, 1 H), 6.42(d, J=1.8 Hz, 1 H), 3.90 (s, 3 H), 3.66 (s, 3 H). MS(ES) [M+H]^(F)285.0.

c) 2,5-Dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoic acid

To a stirred solution of methyl2,5-dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoate (0.35 g, 1.228 mmol)in Methanol (25 mL) was added 1N sodium hydroxide (5.0 ml, 5.00 mmol).The reaction was heated to 40° C. and stirred overnight. LCMS showedthat the reaction was complete. The reaction was evaporated under vacuumto remove the methanol then acidified with 1N HCl (5.0 mL). The solidwhich separated was filtered off washed with water and dried undervacuum to give the product2,5-dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoic acid (299 mg, 1.103mmol, 90% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=13.94 (br. s., 1 H), 7.92 (d, J=2.5 Hz, 1 H), 7.74 (d, J=2.8 Hz, 1 H),7.53 (d, J=2.0 Hz, 1 H), 6.41 (d, J=2.0 Hz, 1 H), 3.65 (s, 3 H). MS(ES)[M+H]⁺ 271.0.

d)2,5-Dichloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-(1-methyl-1H-pyrazol-5-yl)benzamide

To a stirred mixture of 2,5-dichloro-3-(1-methyl-1H-pyrazol-5-yl)benzoicacid (250 mg, 0.922 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-onehydrochloride salt (190 mg, 1.007 mmol) and HOAt (130 mg, 0.955 mmol) inDichloromethane (DCM) (20 mL) was added N-methylmorpholine (110 μL,1.001 mmol) followed by EDC free base (180 mg, 1.159 mmol). The reactionwas stirred at room temperature overnight for 18 hr. Reaction formed athick suspension. LCMS showed that the reaction was complete. Tried topurifiy by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% MeOHin CH₂Cl₂) (Not real soluble in CH₂Cl₂. Used a DASi filter). Most of theproduct remained on the DASi filter. This insoluble material was removedas well as product which streaked off the column, triturated with 10%MeOH in water, filtered, washed with the same and dried under vacuum togive the product2,5-dichloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-5-yl)benzamide(342 mg, 0.844 mmol, 92% yield) as a white solid. The sample for theLCMS was suspended in MeOH with 1 drop of 6N HCl to dissolve. ¹H NMR(400 MHz, DMSO-d₆) δ=11.51 (br. s., 1 H), 8.57 (t, J=4.8 Hz, 1 H), 7.60(d, J=2.5 Hz, 1 H), 7.55 (d, J=2.5 Hz, 1 H), 7.52 (d, J=1.8 Hz, 1 H),6.36 (d, J=1.8 Hz, 1 H), 5.88 (s, 1 H), 4.29 (d, J=4.8 Hz, 2 H), 3.64(s, 3 H), 2.20 (s, 3 H), 2.11 (s, 3 H). MS(ES) [M+H]⁺ 405.1.

Examples 30-41 were prepared by the methods either described above or inthe intermediates section, or routine variations thereof:

MS(ES) Ex Structure Name 1H NMR [M + H]⁺ 30

3-(sec-butoxy)-N- ((4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-2-methyl- 5-(6-(4- methylpiperazin-1- yl)pyridin-3-yl)benzamide 0.94 (t, J = 7.33 Hz, 3 H) 1.25 (d, J = 5.81 Hz, 3 H)1.58-1.73 (m, 2 H) 2.11 (d, J = 3.28 Hz, 6 H) 2.20 (s, 3 H) 2.22 (s, 3H) 2.37- 2.44 (m, 4 H) 3.48-3.56 (m, 4 H) 4.27 (s, 1 H) 4.28 (s, 1 H)4.51-4.60 (m, 1 H) 5.86 (s, 1 H) 6.90 (d, J = 8.84 Hz, 1 H) 7.00 (d, J =1.52 Hz, 1 H) 7.14-7.18 (m, 1 H) 7.84 (dd, J = 8.84, 2.53 Hz, 1 H) 8.19(br. s., 1 H) 8.43 (d, J = 2.27 Hz, 1 H) 11.38 (br. s., 1 H) 518.4 31

5-(sec-butoxy)-N- ((4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-3′- ((dimethylamino)meth- yl)-4-methyl-[1,1′- biphenyl]-3-carboxamide 0.95 (t, J = 7.45 Hz, 3 H) 1.26 (d, J = 6.06 Hz, 3 H)1.62-1.72 (m, 2 H) 2.11 (s, 3 H) 2.13 (s, 3 H) 2.16 (s, 6 H) 2.20 (s, 3H) 3.45 (s, 2 H) 4.28 (s, 1 H) 4.29 (s, 1 H) 4.56 (q, J = 5.98 Hz, 1 H)5.86 (s, 1 H) 7.04 (d, J = 1.52 Hz, 1 H) 7.18 (d, J = 1.52 Hz, 1 H) 7.27(d, J = 7.58 Hz, 1 H) 7.40 (t, J = 7.96 Hz, 1 H) 7.52-7.55 (m, 2 H) 8.25(br. s., 1 H) 11.39 (br. s., 1 H) 476.3 32

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-3-isopropoxy-2-methyl- 5-(6-(piperazin-1- yl)pyridin-3- yl)benzamide 11.48(br. s., 1 H), 8.42 (d, J = 2.5 Hz, 1 H), 8.16 (t, J = 4.9 Hz, 1 H),7.83 (dd, J = 9.0, 2.7 Hz, 1 H), 7.17 (d, J = 1.5 Hz, 1 H), 7.01 (d, J =1.8 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 5.86 (s, 1 H), 4.73 (quin, J =6.1 Hz, 1 H), 4.27 (d, J = 5.1 Hz, 2 H), 3.44 (m, 4 H), 2.78 (m, 4 H),2.20 (s, 3 H), 2.09 (m, 6 H), 1.28 (m, 6 H) 490.4 33

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-3-isopropoxy-2-methyl- 5-(6-(4- methylpiperazin-1- yl)pyridin-3-yl)benzamide 11.47 (s, 1 H), 8.43 (d, J = 2.3 Hz, 1 H), 8.16 (t, J = 4.9Hz, 1 H), 7.84 (dd, J = 8.8, 2.5 Hz, 1 H), 7.17 (m, 1 H), 7.01 (d, J =1.5 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 5.86 (s, 1 H), 4.73 (quin, J =6.0 Hz, 1 H), 4.28 (d, J = 5.1 Hz, 2 H), 3.51 (m, 4 H), 2.40 (m, 4 H),2.21 (d, J = 8.6 Hz, 6 H), 2.09 (m, 6 H), 1.29 (m, 6H) 504.7 34

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-3′-((dimethylamino)meth- yl)-5-isopropoxy-4- methyl-[1,1′- biphenyl]-3-carboxamide 11.46 (s, 1 H), 8.21 (t, J = 4.9 Hz, 1 H), 7.53 (m, 2 H),7.39 (t, J = 7.6 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.20 (m, 1 H),7.05 (d, J = 1.5 Hz, 1 H), 5.86 (s, 1 H), 4.74 (m, 1 H), 4.28 (d, J =4.8 Hz, 2 H), 3.44 (s, 2 H), 2.20 (s, 3 H), 2.16 (s, 6 H), 2.13 (s, 3H), 2.10 (s, 3 H), 1.30 (m, 6 H) 462.4 35

3-(sec-butoxy)-N- ((4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-2-methyl- 5-(6-(piperazin-1- yl)pyridin-3- yl)benzamide 0.94(t, J = 7.33 Hz, 3 H) 1.25 (d, J = 5.81 Hz, 3 H) 1.58-1.72 (m, 2 H) 2.11(d, J = 2.27 Hz, 6 H) 2.20 (s, 3 H) 2.71-2.85 (m, 3 H) 3.40-3.55 (m, 4H) 4.27 (s, 1 H) 4.29 (s, 1 H) 4.52-4.59 (m, 1 H) 5.86 (s, 1 H) 6.86 (d,J = 9.09 Hz, 1 H) 7.00 (d, J = 1.26 Hz, 1 H) 7.13-7.17 (m, 1 H) 7.83(dd, J = 8.84, 2.53 Hz, 1 H) 8.17 (t, J = 4.93 Hz, 1 H) 8.43 (d, J =2.53 Hz, 1 H) 11.49 (br. s., 1 H) 504.4 36

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-3- methoxy-2-methylbenzamide 2.10 (d, J = 4.80 Hz, 6 H) 2.19 (s, 3 H) 3.78 (s, 3 H)4.26 (d, J = 5.05 Hz, 2 H) 5.86 (s, 1 H) 6.81 (d, J = 6.82 Hz, 1 H) 6.97(d, J = 7.83 Hz, 1 H) 7.16 (t, J = 7.96 Hz, 1 H) 8.05 (t, J = 4.93 Hz, 1H) 11.46 (s, 1H) 301.2 37

3-(sec-butoxy)-N- ((4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-2- methylbenzamide 0.93 (t, J = 7.33 Hz, 3 H) 1.22 (d, J =6.06 Hz, 3 H) 1.63 (ddd, J = 11.56, 7.39, 6.06 Hz, 2 H) 2.09 (s, 3 H)2.11 (s, 3 H) 2.19 (s, 3 H) 4.25 (s, 1 H) 4.26 (s, 1 H) 4.34-4.40 (m, 1H) 5.86 (s, 1 H) 6.77 (d, J = 7.33 Hz, 1 H) 6.96 (d, J = 8.08 Hz, 1 H)7.11 (t, J = 7.83 Hz, 1 H) 8.04 (t, J = 4.93 Hz, 1 H) 11.46 (br. s., 1H) 343.2 38

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-3-isopropoxy-2- methylbenzamide 1.25 (s, 3 H) 1.27 (s, 3 H) 2.08 (s, 3 H)2.11 (s, 3 H) 2.19 (s, 3 H) 4.25 (s, 1 H) 4.26 (s, 1 H) 4.57 (dt, J =12.06, 5.97 Hz, 1 H) 5.86 (s, 1 H) 6.78 (d, J = 6.82 Hz, 1 H) 6.98 (d, J= 8.08 Hz, 1 H) 7.12 (t, J = 7.83 Hz, 1 H) 8.03 (t, J = 4.93 Hz, 1 H)11.46 (br. s., 1 H) 329.2 39

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-2-methyl-3-((tetrahydrofuran-3- yl)oxy)benzamide 1.91-1.99 (m, 1 H) 2.09 (s, 3 H)2.11 (s, 3 H) 2.15- 2.24 (m, 4 H) 3.74-3.87 (m, 3 H) 3.90 (dd, J =10.11, 4.55 Hz, 1 H) 4.25 (s, 1 H) 4.26 (s, 1 H) 4.99-5.06 (m, 1 H) 5.86(s, 1 H) 6.82 (d, J = 7.07 Hz, 1 H) 6.96 (d, J = 8.08 Hz, 1 H) 7.14 (t,J = 7.83 Hz, 1 H) 8.06 (t, J = 4.93 Hz, 1 H) 11.46 (s, 1 H) 357.1 40

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-2-methyl-3-((1- methylpyrrolidin-3- yl)oxy)benzamide 1.76 (ddd, J = 12.57, 6.63,2.78 Hz, 1 H) 2.08 (s, 3 H) 2.11 (s, 3 H) 2.19 (s, 3 H) 2.24-2.29 (m, 4H) 2.35-2.41 (m, 1 H) 2.56 (dd, J = 10.36, 2.78 Hz, 1 H) 2.61-2.67 (m, 1H) 2.80 (dd, J = 10.36, 6.06 Hz, 1 H) 4.25 (s, 1 H) 4.26 (s, 1 H)4.82-4.87 (m, 1 H) 5.85 (s, 1 H) 6.79 (d, J = 6.82 Hz, 1 H) 6.88 (d, J =8.08 Hz, 1 H) 7.09-7.14 (m, 1 H) 8.05 (t, J = 4.93 Hz, 1 H) 11.44 (br.s., 1 H) 370.2 41

N-((4,6-dimethyl-2- oxo-1,2- dihydropyridin-3- yl)methyl)-2-methyl-3-((tetrahydro-2H- pyran-4- yl)oxy)benzamide 1.61 (m, J = 12.82, 8.53,4.11, 4.11 Hz, 2 H) 1.90- 1.98 (m, 2 H) 2.11 (s, 3 H) 2.13 (s, 3 H) 2.19(s, 3 H) 3.50 (ddd, J = 11.49, 8.46, 3.03 Hz, 2 H) 3.79- 3.85 (m, 2 H)4.25 (s, 1 H) 4.27 (s, 1 H) 4.57 (dt, J = 7.89, 4.01 Hz, 1 H) 5.86 (s, 1H) 6.79-6.83 (m, 1 H) 7.04 (d, J = 7.58 Hz, 1 H) 7.12 (t, J = 7.83 Hz, 1H) 8.05 (t, J = 4.93 Hz, 1 H) 11.46 (br. s., 1 H) 371.5

Example 423-(sec-Butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(methylsulfonyl)benzamide

In a microwave vial, copper(II) trifluoromethanesulfonate (86 mg, 0.237mmol) and methanesulfinate, sodium salt (57.0 mg, 0.475 mmol) weredissolved in dimethyl sulfoxide (DMSO) (2 mL). The solution stirredunder nitrogen for 10 min before, at which time was addedN1,N2-dimethylethane-1,2-diamine (0.054 mL, 0.498 mmol) and5-bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(100 mg, 0.237 mmol). The dark blue clear solution was stirred at 120°C. for 2 hours. The LCMS spectrum of the crude mixture showed 52%conversion into desired product. 43 mg of copper(II)trifluoromethanesulfonate, 38 mg of methanesulfinate, sodium salt and 27μL of N1,N2-dimethylethane-1,2-diamine were added and the deep bluesolution was stirred at 120° C. for 1.75 h, then at room temperature for4 days. The mixture was purified by Gilson reversed-phase HPLC (30×100Varian Polaris C_(18, 3)-70% gradient of MeCN in water with 0.1% TFAover 12 minutes) to give3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(methylsulfonyl)benzamide(44.6 mg, 0.105 mmol, 44.2% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 0.94 (t, J=7.33 Hz, 3 H) 1.26 (d, J=6.06 Hz, 3 H) 1.63-1.72(m, 2 H) 2.12 (s, 3 H) 2.17 (s, 3 H) 2.20 (s, 3 H) 3.21 (s, 3 H) 4.28(s, 1 H) 4.29 (s, 1 H) 4.56 (q, J=5.81 Hz, 1 H) 5.87 (s, 1 H) 7.29 (d,J=1.52 Hz, 1 H) 7.40 (d, J=1.77 Hz, 1 H) 8.38 (t, J=4.93 Hz, 1 H) 11.50(s, 1 H). MS(ES) [M+H]⁺ 421.3.

Example 43N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methyl-5-(methylsulfonyl)benzamide

Following the procedure described in Example 42, the title compound wasprepared (20 mg, 31% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.20 (s, 3 H)1.21 (s, 3 H) 2.08 (s, 3 H) 2.11 (s, 3 H) 2.19 (s, 3 H) 3.13 (s, 3 H)3.70 (s, 1 H) 4.27 (s, 1 H) 4.28 (s, 1 H) 5.02 (d, J=8.08 Hz, 1 H) 5.87(s, 1 H) 6.91 (d, J=1.52 Hz, 1 H) 6.94-6.97 (m, 1 H) 8.23 (t, J=4.93 Hz,1 H) 11.48 (br. s., 1 H). MS(ES) [M+H]⁺ 406.3.

Example 443-(sec-Butoxy)-5-cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide

5-Bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(100 mg, 0.24 mmol), dicyanozinc (32 mg, 0.27 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (29.1 mg, 0.04 mmol), Dppf (32.9 mg, 0.06 mmol) and zinc (3.9 mg,0.06 mmol) in 3 mL of DMA were degassed for 10 min and sealed in amicrowave vial. The mixture was heated to 120° C. for 19 hours. Thereaction was allowed to cool to ambient temperature, quenched with waterand stirred for 1 h. The resulting precipitate was filtered, dissolvedin DCM/MeOH (1:1), preabsorbed on silica gel and purified using normalphase chromatography: DCM/(40 g, gradient 0 to 80:20:2 in DCM) to give abrown oil. EtOAc was added (along with some hexanes) and the resultingprecipitate was filtered, air-dried for 15 min, and dried in vaccum-ovenovernight to give the title compound (46 mg, 53% yield). ¹H NMR (400MHz, DMSO-d₆) δ 0.92 (t, J=7.45 Hz, 3 H) 1.23 (d, J=6.06 Hz, 3 H)1.57-1.71 (m, 2 H) 2.11 (s, 3 H) 2.14 (s, 3 H) 2.17-2.21 (m, 3 H) 4.25(s, 1 H) 4.26 (s, 1 H) 4.53 (q, J=6.06 Hz, 1 H) 5.86 (s, 1 H) 7.21 (d,J=1.26 Hz, 1 H) 7.45 (d, J=1.26 Hz, 1 H) 8.33 (t, J=5.05 Hz, 1 H) 11.48(br. s., 1 H). MS(ES) [M+H]⁺ 368.3.

Example 455-Cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-2-methylbenzamide

Following the procedure described in Examples 44 and 1, the titlecompound was prepared. ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 3 H) 1.28(s, 3 H) 2.11 (s, 3 H) 2.13 (s, 3 H) 2.19 (s, 3 H) 4.25 (s, 1 H) 4.26(s, 1 H) 4.68-4.76 (m, 1 H) 5.87 (s, 1 H) 7.22 (d, J=1.26 Hz, 1 H) 7.47(d, J=1.26 Hz, 1 H) 8.33 (t, J=4.93 Hz, 1 H) 11.49 (br. s., 1 H). MS(ES)[M+H]⁺ 354.2.

Example 463-(sec-Butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-2-methylbenzamide

To5-bromo-3-(sec-butoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide(130 mg, 0.31 mmol) and copper(I) iodide (70.5 mg, 0.37 mmol) was addedN-methyl-2-pyrrolidone (NMP) (3 mL). To the mixture was added dropwise asolution of 25 wt % sodium methoxide in MeOH (0.28 mL, 1.23 mmol) withstirring. The reaction was heated to 120° C. and stirred for 36 h. Thereaction mixture was then diluted with water and EtOAc was added. Themixture was filtered through Celite and washed with EtOAc. The filtratewas poured into a separatory funnel, the organic phase was separated,washed with brine, dried over MgSOl₄, filtered, and concentrated undervacuum. The residue was purified by Gilson reversed-phase HPLC (30×100Varian Polaris C18, 20-70% gradient of MeCN in water with 0.1% TFA over12 minutes). Most of the solvent was evaporated and sat. aq. NaHCO₃ wasadded. The solids that crashed out were filtered, air-dried for 15 minand dried in vaccum-oven overnight to give the title compound (24 mg,20% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 0.92 (t, J=7.45 Hz, 3 H) 1.21(d, J=6.06 Hz, 3 H) 1.55-1.68 (m, 2 H) 1.96-2.04 (m, 3 H) 2.08-2.13 (m,3 H) 2.18 (s, 3 H) 3.68-3.76 (m, 3 H) 4.25 (d, J=5.05 Hz, 2 H) 4.37(sxt, J=5.96 Hz, 1 H) 5.86 (s, 1 H) 6.36 (d, J=2.27 Hz, 1 H) 6.52 (d,J=2.27 Hz, 1 H) 8.03 (t, J=4.93 Hz, 1 H) 11.47 (s, 1 H). MS(ES) [M+H]⁺373.2.

Example 47N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropoxy-5-methoxy-2-methylbenzamide

Following the procedure described in Examples 46 and 1, the titlecompound was prepared. ¹H NMR (400 MHz, DMSO-d₆) δ 1.24 (s, 3 H) 1.26(s, 3 H) 1.99 (s, 3 H) 2.11 (s, 3 H) 2.18 (s, 3 H) 3.72 (s, 3 H) 4.24(s, 1 H) 4.25 (s, 1 H) 4.54-4.60 (m, 1 H) 5.86 (s, 1 H) 6.37 (d, J=2.27Hz, 1 H) 6.55 (d, J=2.53 Hz, 1 H) 8.04 (t, J=4.93 Hz, 1 H). MS(ES)[M+H]⁺ 359.2.

Example 48N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methylbenzamide

To a mixture of5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methylbenzamide(84.7 mg, 0.208 mmol) in EtOAc (3 mL), THF (1 mL), MeOH (0.5 mL) andtriethylamine (0.5 mL) was added Pd/C (10% wet Degussa type; 22 mg, 0.21mmol). The insoluble mixture was stirred under a balloon of hydrogen atroom temperature for 1.5 h. LCMS showed 16% conversion. The mixture wasthen stirred at room temperature for 18 h. LCMS showed no change. MorePd/C was added and the reaction was stirred at room temperature for 5 h.LCMS showed only 32% conversion. DMF (0.5 mL) was added to try tosolubilize the compound and the reaction solution was filtered throughcelite, washed with ethyl acetate and evaporated. The residue wasdissolved in a mixture of EtOAc (4 mL). THF (1.6 mL) and DMF (0.5 mL)(The mixture was first a clear solution but after 10 minutes, some solidstarted crystallizing) and hydrogenated again using Pd/C (10% wetDegussa type; 22 mg, 0.21 mmol) and a balloon of hydrogen. It wasstirred at room temperature overnight. LCMS showed 35% conversion. Thereaction mixture was filtered through celite, washed with EtOAc and thefiltrate was evaporated. The residue was dissolved in EtOH andhydrogenated using H-Cube hydrogenation reactor during 4 hours atambient pressure. LCMS showed complete conversion.

The reaction mixture was evaporated to give a dark black resiude, whichwas dissolved in EtOH and filtered through Acrodisk 13 CR PTFE 0.2 μm toremove the residual palladium. The solution was evaporated. Purificationof the residue by normal phase chromatography DCM/MeOH/NH₄OH (12 g Goldcolumn, gradient 0 to 80:20:2 in DCM) gaveN-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(isopropylamino)-2-methylbenzamide(10.2 mg, 0.030 mmol, 14.50% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.16(s, 3 H) 1.17 (s, 3 H) 2.00 (s, 3 H) 2.11 (s, 3 H) 2.19 (s, 3 H) 3.61(dd, J=13.89, 6.32 Hz, 1 H) 4.24 (s, 1 H) 4.25 (s, 1 H) 4.36 (d, J=8.08Hz, 1 H) 5.85 (s, 1 H) 6.44 (d, J=6.82 Hz, 1 H) 6.58 (d, J=8.08 Hz, 1 H)6.98 (t, J=7.83 Hz, 1 H) 7.88 (t, J=4.93 Hz, 1 H) 11.45 (br. s., 1 H.MS(ES) [M+H]⁺ 328.2.

Assay Protocol

Compounds contained herein were evaluated for their ability to inhibitthe methyltransferase activity of EZH2 within the PRC2 complex. HumanPRC2 complex was prepared by co-expressing each of the 5 member proteins(FLAG-EZH2, EED, SUZ12, RbAp48, AEBP2) in Sf9 cells followed byco-purification. Enzyme activity was measured in a scintillationproximity assay (SPA) where a tritiated methyl group is transferred from3H-SAM to a lysine residue on Histone H3 of a mononucleosome, purifiedfrom HeLa cells. Mononucleosomes were captured on SPA beads and theresulting signal is read on a ViewLux plate reader.

Part A. Compound Preparation

-   1. Prepare 10 mM stock of compounds from solid in 100% DMSO.-   2. Set up an 11-point serial dilution (1:3 dilution, top    concentration 10 mM) in 100% DMSO for each test compound in a 384    well plate leaving columns 6 and 18 for DMSO controls.-   3. Dispense 100 nL of compound from the dilution plate into reaction    plates (Grenier Bio-One, 384-well, Cat #784075).    Part B. Reagent Preparation    Prepare the Following Solutions:-   1. 50 mM Tris-HCl, pH 8: Per 1 L of base buffer, combine 1 M    Tris-HCl, pH 8 (50 mL) and distilled water (950 mL).-   2. 1× Assay Buffer: Per 10 mL of 1× Assay Buffer, combine 50 mM    Tris-HCl, pH 8 (9958 uL), 1 M MgCl₂ (20 uL), 2 M DTT (20 uL), and    10% Tween-20 (2 uL) to provide a final concentration of 50 mM    Tris-HCl, pH 8, 2 mM MgCl₂, 4 mM DTT, 0.002% Tween-20.-   3. 2× Enzyme Solution: Per 10 mL of 2× Enzyme Solution, combine 1×    Assay Buffer and PRC2 complex to provide a final enzyme    concentration of 10 nM.-   4. SPA Bead Suspension: Per 1 mL of SPA Bead Suspension, combine    PS-PEI coated LEADSeeker beads (40 mg) and ddH₂O (1 mL) to provide a    final concentration of 40 mg/mL.-   5. 2× Substrate Solution: Per 10 mL of 2× Substrate Solution,    combine 1× Assay Buffer (9728.55 uL), 800 ug/mL mononucleosomes (125    uL), 1 mM cold SAM (4 uL), and 7.02 uM 3H-SAM (142.45 uL; 0.55    mCi/mL) to provide a final concentration of 5 ug/mL nucleosomes, 0.2    uM cold SAM, and 0.05 uM 3H-SAM.-   6. 2.67× Quench/Bead Mixture: Per 10 mL of 2.67× Quench/Bead    Mixture, combine ddH₂O (9358 uL), 10 mM cold SAM (267 uL), 40 mg/mL    Bead Suspension (375 uL) to provide a final concentration of 100 uM    cold SAM and 0.5 mg/mL SPA beads.    Part C. Assay Reaction in 384-Well Grenier Bio-One Plates    Compound Addition-   1. Dispense 100 nL/well of 100× Compound to test wells (as noted    above).-   2. Dispense 100 nL/well of 100% DMSO to columns 6 & 18 for high and    low controls, respectively.    Assay-   1. Dispense 5 uL/well of 1× Assay Buffer to column 18 (low control    reactions).-   2. Dispense 5 uL/well of 2× Enzyme Solution to columns 1-17, 19-24.-   3. Spin assay plates for ˜1 minute at 500 rpm.-   4. Stack the assay plates, covering the top plate.-   5. Incubate the compound/DMSO with the enzyme for 30 minutes at room    temperature.-   6. Dispense 5 uL/well of 2× Substrate Solution to columns 1-24.-   7. Spin assay plates for ˜1 minute at 500 rpm.-   8. Stack the assay plates, covering the top plate.-   9. Incubate the assay plates at room temperature for 1 hour.    Quench/Bead Addition-   1. Dispense 5 uL/well of the 3× Quench/Bead Mixture to columns 1-24.-   2. Seal the top of each assay plate with adhesive TopSeal.-   3. Spin assay plates for ˜1 minute at 500 rpm.-   4. Equilibrate the plates for >20 min.    Read Plates-   1. Read the assay plates on the Viewlux Plate Reader utilizing the    613 nm emission filter with a 300 s read time.    Reagent addition can be done manually or with automated liquid    handler.-   The final DMSO concentration in this assay is 1%.-   The positive control is in column 6; negative control is in column    18.-   Final starting concentration of compounds is 100 μM.    Results

Percent inhibition was calculated relative to the DMSO control for eachcompound concentration and the resulting values were fit using standardIC₅₀ fitting parameters within the ABASE data fitting software package.

Exemplified compounds of the present invention were generally testedaccording to the above or an analogous assay and were found to beinhibitors of EZH2. The IC₅₀ values ranged from about 13 nM to about 2.5μM; The IC₅₀ values of the more active compounds range from about 1 nMto about 500 nM; The most active compounds are under 50 nM. Examplarcompounds with specific biological activities tested according to assaysdescribed herein are listed in the following table. Repeating the assayrun(s) may result in a somewhat different.

Example EZH2 IC50(nM) 1 501 2 40 4 50 24 250 20 13 26 1000 36 2500 44316

The invention claimed is:
 1. A method of treating a hematologic cancercomprising administering to a patient with cancer a therapeuticallyeffective amount of a compound of formula (I):

wherein: R¹ is methyl; R² is methyl; R³ is hydrogen; R⁴ is methyl; R⁵ is—NR^(a)R^(b); R⁶ is phenyl, wherein said phenyl is optionallysubstituted by —(C₁-C₆)alkyl(R^(c)); R^(c) is —NR^(a)R^(b); and R^(a)and R^(b) are each independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₈)cycloalkenyl,heterocycloalkyl, or aryl, wherein said (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or arylgroup is optionally substituted by 1, 2 or 3 groups independentlyselected from the group consisting of halo, hydroxyl, (C₁-C₄)alkoxy,amino, (C₁-C₄)alkylamino, —N((C₁-C₄)alkyl)₂, —CO₂H, —CO₂(C₁-C₄)alkyl,—CONH₂, —CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)₂, —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)₂; and wherein saidheterocycloalkyl is selected from the group consisting of pyrrolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, and tetrahydropyranyl; or R^(a) and R^(b) takentogether with the nitrogen to which they are attached represent a 5 or 6membered saturated ring, optionally containing an additional heteroatomselected from oxygen, nitrogen, and sulfur, wherein said ring isoptionally substituted by 1, 2 or 3 groups independently selected fromthe group consisting of (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino,(C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo,(C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein saidhematologic cancer is selected from the group consisting of: acutemyeloid leukemia, chronic myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome, and Hodgkin's disease.